Antimicrobial drug synthesis and therapeutic compositions

ABSTRACT

This invention relates to the medical use of an antimicrobial agent, racemic Ornidazole, its (R) and (S) enantiomers, or pharmaceutically acceptable salts or esters thereof, and to methods of treatment which involve treating a subject with Ornidazole. The racemic (rac)-ornidazole, its enantiomers, or pharmaceutically acceptable salts or esters thereof, may be used in combination with other actives. The invention also relates to pharmaceutical formulations and compositions comprising (rac)-ornidazole, (R)-ornidazole, (S)-ornidazole, or pharmaceutically acceptable salts or esters thereof, and/or other actives as well as methods to stereoselectively manufacture the enantiomers.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) to: U.S.Provisional Application Ser. No. 62/124,467 filed Dec. 20, 2014; U.S.Provisional Application Ser. No. 62/124,468, filed Dec. 20, 2014, U.S.Provisional Application Ser. No. 62/124,469, filed Dec. 20, 2014, U.S.Provisional Application Ser. No. 62/124,470, filed Dec. 20, 2014, U.S.Provisional Application Ser. No. 62/124,471, filed Dec. 20, 2014, U.S.Provisional Application Ser. No. 62/124,472, filed Dec. 20, 2014, all ofwhich are incorporated herein by reference in their entireties.

BACKGROUND

ORNIDAZOLE is a nitroimidazole anti-infective. Its systematic (IUPAC)name is 1-chloro-3-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol andits chemical formula is C₇H₁₀ClN₃O₃. Ornidazole contains a single chiralcentre and thus exists as either the S-enantiomer or the R-enantiomer.

Both the (R)-ornidazole enantiomer (hereinafter referred to as,“(R)-ornidazole”), and the (S)-ornidazole enantiomer (hereinafterreferred to as, “(S)-ornidazole”) have both different and uniqueindividual spectrums of activity as well as pharmacological & safetyadvantages over racemic ornidazole (rac)-ornidazole). (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole are new chemical entities (NCEs) inthe United States and have not been marketed in this jurisdiction orcleared by the Food & Drug Administration (FDA).

The beneficial properties of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole include a favorable pharmacokinetic and pharmacodynamicprofile and high degree of susceptibility to pathogenic strains ofbacteria when the right (minimum inhibitory or bacteriocidal) drugconcentrations are employed at the site of infections. In addition,(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are effective attreating and eradicating bacterial biofilms of many pathogens that havesensitivity in their planktonic forms at lower MICs than the biofilmform. Many bacterial species are inducible facultative niorphologs. Aninducible facultative morpholog species can reversibly changeconfiguration from planktonic to biofilm forms and morphologicalintermediates (such as round body/cystic/and spore forms) based onenvironmental conditions and through quorum sensing mediated by chemicalsignalling.

These inducible morphologies, e.g., biofilms and their intermediateforms, have MICs that can be orders of magnitude higher than theplanktonic forms of the bacteria. The lethal dose of the antibiotics forbacteria in the biofilm form is called the “minimal bacterialeradication concentration” or “MBEC”. The ability of the bacteria toshift into a biofilm form serves as an antimicrobial resistance (AMR)mechanism for usually adminstered dosages or antimicrobials.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highlyeffective in treating biofilms bacterial configurations that thesebacteria utilize to combat therapeutics and maintain recurrencereservoirs. The microorganisms in biofilms live in a self-producedmatrix of hydrated extracellular polymeric substances (EPS) that formtheir immediate environment. EPS are mainly polysaccharides, proteins,nucleic acids and lipids; they provide the mechanical stability ofbiofilms, mediate their adhesion to surfaces and form a cohesive,three-dimensional polymer network that interconnects and transientlyimmobilizes biofilm cells. In addition, the biofilm matrix acts as anexternal digestive system by keeping extracellular enzymes close to thecells, enabling them to metabolize dissolved, colloidal and solidbiopolymers.

Planktonic isolates are susceptible to common antibiotics. Strains inbiofims and anaerobic configurations are markedly resistant to manyantimicrobial agents. However, many of these biofilms and perisistorcells within the biofilm are sensitive to (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole when exposed to a MBEC and whenused in combination with monosaccharides and oligosaccharides thatincrease the metabolic activity of the cells within the biofilmincreasing antimicrobial uptake and toxicity.

Thus, the use of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolemay provide a number of advantages including, for example, formulationstargeting the site of infections or dysbiosis/bacterial overgrowth inbiofilms or formulations utilizing smaller amounts of the active drugthan alternative treatments, so that patients can ingest smaller tabletsor capsules, or allowing the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole to be combined with other active agent(s) in a singleunit dosage form; allowing more convenient dosing schedules andincreasing patient compliance. For example, (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole are rapidly absorbed after oraladministration and have a longer terminal elimination half-life(approximately 14-18 hours) than commonly used drugs in the imidazoleclass. Accordingly these drugs may be administered less frequentlyand/or at a lower dose, thus improving patient compliance whileproviding a therapeutically effective treatment of an infection.

Additionally, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole aremore active than metronidazole, another nitro-imidazole usedtherapeutically, for many anaerobic and aerobic bacterial strains(including both Gram positive and Gram negative strains). Even againststrains in which (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare as active, or even less active than metronidazole, they still offersother benefits.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are active againstboth susceptible and resistant strains of anaerobic or aerobic, Gramnegative or Gram positive bacteria. Resistant strains of a specificbacteria are strains of that bacteria which are resistant to one or moredrugs normally used to treat bacterial infections, e.g. strains ofbacteria which are resistant to metronidazole.

For many bacterial strains and parasitic protozoal organisms(R)-ornidazole and (S)-ornidazole are more active than (rac)-ornidazole.Likewise, for many bacterial strains and parasitic protozoal organisms,(R)-ornidazole and (S)-ornidazole are more active than (rac)-Ornidazole.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole also conferscertain specific efficacy and safety benefits. For example Ornidazoleappears to be free of inductive and inhibitory activity against CYPenzymes know to cause drug-drug interaction problems, does not have adisulfiram like interaction with alcohol that has been associated withother nitro-imidazoles, and is not a carcinogen.

SUMMARY OF THE INVENTION

The present invention relates to methods of treating and/or reducing theincidence of various diseases by administering to a subject in needthereof a therapeutically effective amount of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, or pharmaceutically acceptablesalts or esters thereof. In some embodiments, (R)-ornidazole and(S)-ornidazole, or pharmaceutically acceptable salts or esters thereof,have an enantiomeric purity of at least about 50% enantiomeric excess(ee), at least about 60% enantiomeric excess (ee), at least about 70%enantiomeric excess (ee), at least about 80% enantiomeric excess (ee),at least about 90% enantiomeric excess (ee), at least about 95%enantiomeric excess (ee), at least about 96% enantiomeric excess (ee),at least about 97% enantiomeric excess (ee), at least about 98%enantiomeric excess (ee), or at least about 99% enantiomeric excess(ee).

The methods of the present invention also include treating a diseaseassociated with a gastrointestinal, abdominal or intra-abdominalinfection; the method comprising administering to a subject in needthereof a therapeutically effective amount of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, or pharmaceutically acceptablesalts or esters thereof. In many cases, the therapeutically effectiveamount of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, for treating theplanktonic form of relevant bacteria is lower than the amount necessaryto achieve a higher concentration that is the MBEC for a biofilm of thatbacteria. Anotherwords, the microbiological breakpoints are differentand a totally different dosing strategy is needed based on theassessment of the MBEC rather than the in-vitro planktonic MIC. In thiscontext, when discussing the therapeutically effective amount of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, it is meant theamount necessary to treat and kill the bacteria within the biofilm, notmerely the planktonic bacteria, and this may sometimes require theco-administration of an oligosaccarharide or monosaccharide to increasethe metabolism of the bacteria within the biofilm to make(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole more effective.

In a specific embodiment, the diseases treated by (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole are caused by a bacterialinfection.

Another embodiment of the invention includes a method of treating adisease associated with a gastrointestinal, abdominal or intra-abdominalinfection; the method comprising administering to a subject in needthereof a therapeutically effective amount of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, or pharmaceutically acceptablesalts or esters thereof.

In another specific embodiment, the disease is one or more diseasesselected from the group consisting of complicated and uncomplicateddiverticulitis, psuedomembranous colitis, biofilms of toxigenic C.difficile infection including C. difficile which are sporulating and ina spore or hard round-body morphological configuration, or a biofilmconfiguration that may be more resistant to concentrations of bacteriadetermined in vitro assessing the planktonic form of the bacteria,infectious/Clostridium difficile-associated diarrhea including thosewhich are toxigenic strains of C. difficile which are sporulating and ina spore or hard round-body morphological configuration and biofilmconfiguration that may be more resistant to concentrations of bacteriadetermined in vitro assessing the planktonic form of the bacteria,cholangitis, cholecystitis, pancreatitis, peritonitis,intra-abdominal/bowel/pelvic/liver abscess (non-protozoal in origin),ulcerative colitis, chronic gastritis, gastric cancer, colorectalcancer, ulcerative colitis, peptic ulcers, gastroduadenal ulcers, andCrohn's Disease.

Thus, the disease that may be treated by (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole may be one or more diseases selected from the groupconsisting of complicated and uncomplicated diverticulitis,psuedomembranous colitis, toxigenic C. difficile infection, toxigenic C.difficile associated diarrhea and accompanying gastroenteritis,cholangitis, cholecystitis, pancreatitis, peritonitis,intra-abdominal/bowel/pelvic/liver abscess, chronic gastritis, gastriccancer, colorectal cancer ulcerative colitis, peptic ulcers,gastroduadenal ulcers, and Crohn's Disease.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare for use in treating a condition selected from H. Pylori infection inbiofilm configuration, gastric, dental biofilm (plaque), abdominal andintra-abdominal infections as well as infections with the bacteria inplanktonic and intermediate forms.

In an embodiment, the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are for use in treating protozoa infections. In afurther embodiment, the protozoa infection is selected from: giardiasisand amoebiasis (e.g. that caused by Entamoeba histolytica).

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may also be used intreating trichmoniasis. The trichmoniasis infection may be in men orwomen.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may also be used intreating diverticulitis (e.g. complicated diverticulitis).(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst both planktonic and biofilm morphologies of the followingbacteria: Helicobacter pylori, Bacteroides species, Fusobacteriumspecies, Clostridium species, Peptococcus species, Peptostreptococcusspecies, Eubacterium species, and Prevotella species. These bacterialspecies are commonly associated with diverticulitis. In particular,(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole have excellentactivity against biofilms of Bacteroides fragilis.

In another embodiment the disease is either complicated or uncomplicateddiverticulitis which have different treatment paradigms.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may be used in thetreatment of C. difficile biofilm infection and may also be used in thetreatment of a condition selected from Clostridium difficile colitis,infectious diarrhea (e.g. C. diff. associated diarrhea (CDAD)), colitis,mucous colitis, and pseudomembranous colitis. These conditions are oftencaused by C difficile biofilm infections as well as planktonic forms andintermediates. (R)-ornidazole has excellent activity against C difficileand in this invention can be delivered in concentrations high enough tobe efficacious for different morphological forms of the bacteria at thesite of infection.

In another specific embodiment, the gastrointestinal infection is causedby biofilms of one or more organisms selected from the group consistingof Prevotella species, Bacteroides species, Clostridium species,Fusobacterium species, Helicobacter pylori, resistant Helicobacterpylori, Peptococcus species and Peptostreptococcus species.

In another specific embodiment, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof, are administered in combination with a therapeuticallyeffective amount of one or more other antibiotics for gastrointestinaldiseases selected from the group consisting of complicated anduncomplicated diverticulitis, irritable bowel syndrome, pseudomembranouscolitis, toxigenic C. difficile infection including C. difficile whichare biofilms, sporulating and in a spore or hard round-bodymorphological configuration that may be more resistant to concentrationsof bacteria determined in vitro assessing the planktonic form of thebacteria, infectious/Clostridium difficile-associated diarrhea includingthose which are toxigenic strains of C. difficile which are biofilms,sporulating and in a spore or hard round-body morphologicalconfiguration that may be more resistant to concentrations of bacteriadetermined in vitro assessing the planktonic form of the bacteria,cholangitis, cholecystitis, pancreatitis, peritonitis,intra-abdominal/bowel/pelvic/liver abscess (non-protozoal in origin),ulcerative colitis, chronic gastritis, gastric cancer, colorectal cancerand ulcerative colitis.

Irritable bowel syndrome (IBS) or “spastic colon” is a symptom-baseddiagnosis characterized by chronic abdominal pain, discomfort, bloating,and alteration of bowel habits. Diarrhea or constipation maypredominate, or they may alternate (classified as IBS-D, IBS-C, orIBS-A, respectively). Abnormalities in the gut flora consisting ofbiofilms and planktonic forms that can be modulated with antibioticslike (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole result ininflammation and altered bowel function.

Cholangitis, including ascending cholangitis or acute cholangitis isusually caused by bacteria ascending from the junction stomach with theduodenum (first part of the small intestine) forming biofilms. It tendsto occur if the bile duct is already partially obstructed by gallstones.

Cholecystitis is inflammation of the gallbladder. Cholecystitis occursmost commonly due to blockage of the cystic duct with gallstones(cholelithiasis).

In another embodiment, the one or more other antibiotics for thegastrointestinal infections are selected from tetracycline antibiotics,macrolide antibiotics, quinolone antibiotics, β-lactam antibiotics andpenem antibiotics for co-administration/combination with one of theOrnidazole forms of (R)-ornidazole, (S)-ornidazole, or (rac)-ornidazole.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may also be used intreating both planktonic and biofilm abdominal and intra-abdominalinfections, e.g. severe abdominal and intra-abdominal infections incombination with one or more other antibiotics for gastrointestinalinfections. These antibiotics are selected from tetracyclineantibiotics, macrolide antibiotics, quinolone antibiotics, β-lactamantibiotics and penem antibiotics.

Abdominal and intra-abdominal infections are mixed infections of grampositive and gram negative aerobic and anaerobic bacteria that typicallyneed antibiotics from several classes to cover all of the potentiallypathogenic organism. Specific examples of such abdominal andintra-abdominal infections caused by bacterial biofilms as well asplanktonic morphologies include peritonitis, intra-abdominal abscess,and liver abscess. (R)-ornidazole is highly active against bothplanktonic forms and biofilms of bacterial species including Bacteroidesfragilis, Fusobacterium species, Clostridium species, Peptococcusspecies, Peptostreptococcus species, Eubacterium species, Prevotellaspecies. These bacterial species are commonly associated with the abovementioned abdominal and intra-abdominal infections. In particular,(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole have excellentactivity against biofilms of Bacteroides fragilis and bacteria that arefacultative in their respiration mechanism and morphology.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may also be used intreating gastroenteritis and chronic gastritis in combination with oneor more other antibiotics for gastrointestinal infections where thereare mucosal biofilms interacting with epithelial cells. Theseantibiotics are selected from tetracycline antibiotics, macrolideantibiotics, quinolone antibiotics, β-lactam antibiotics and penemantibiotics.

Gastroenteritis or infectious diarrhea is a medical condition frominflammation of the gastrointestinal tract that involves both thestomach and the small intestine. It causes some combination of diarrhea,vomiting, and abdominal pain and cramping often due to the shedding ofplanktonic bacteria from biofilms which are sensitive to (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole.

Chronic gastritis is a histopathologic entity characterized by chronicinflammation of the stomach mucosa caused by bacterial biofilmirritation.

Peptic ulcers and gastroduadenal ulcers are caused by biofilms of H.pylori that are sensitive to (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole which thus can be used to treat or reduce the incidenceof these infections in another specific embodiment.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may also be used intreating Crohn's Disease and ulcerative colitis in combination with oneor more other antibiotics for gastrointestinal biofilm infections. Theseantibiotics are selected from tetracycline antibiotics, macrolideantibiotics, quinolone antibiotics, f-lactam antibiotics and penemantibiotics.

Ulcerative colitis is a form of colitis, a disease of the colon thatincludes characteristic ulcers, or open sores. The main symptom ofactive disease is usually constant diarrhea mixed with blood, of gradualonset. The chronic inflammation of the colon mucosa is caused bybacterial biofilm irritation from anaerobes, aerobes, and facultativebacteria.

The methods of the present invention also include treating and/orreducing the incidence of cancer associated with a bacterial biofilminfection; the method comprising administering to a subject in needthereof a therapeutically effective amount of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, or pharmaceutically acceptablesalts or esters thereof. The cancers are selected from gastric andcolo-rectal cancer and some of the causative pathogens include biofilmsof Helicobacter pylori for gastric cancer and biofilms of Fusobacteriumspecies for colo-rectal cancer.

Another embodiment of the invention includes a method of treatmentand/or prophylaxis of cancer associated with a bacterial infectionincluding those infections in a biofilm configuration; the methodcomprising administering to a subject in need thereof a therapeuticallyeffective amount of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or esters thereofthat have activity against organisms associated with cancer such asHelicobacter pylori in gastric cancer and Fusobacterium speciesassociated with colorectal cancer.

In a specific embodiment, the cancer is colonic cancer or gastriccancer. In another specific embodiment, the planktonic or bacterialbiofilm infection is caused by one or more organisms selected from thegroup consisting of Fusobacterium species, Helicobacter Pylori,Peptococcus species and Peptostreptococcus species.

The methods of the present invention also include treating adermatological condition the method comprising administering to asubject in need thereof a therapeutically effective amount of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof.

Another embodiment of the invention includes a method of treating adermatological condition; the method comprising administering to asubject in need thereof a therapeutically effective amount of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof.

In a specific embodiment of the present invention, the dermatologicalcondition is from one or more conditions selected from the groupconsisting of acne, rosacea, cellulitis, wound infections (e.g.gangrene), boils, cysts, abscesses, fungating tumors, burns, anddecubitus ulcers (bed sores).

In an embodiment, the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are for use in treating a dermatological condition.Exemplary dermatological conditions which can be treated using(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole include one of moreof acne, rosacea, fungating tumors, and decubitus ulcers (bed sores).

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may also be used insystemic or topical form for the treatment of rosacea. Rosacea has beenassociated with an inflammation causing mite that feeds on biofilms ofBacillus oleronius in the pores of human skin.

Another embodiment of the invention includes therapeutic uses of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, in different oral,topical, and parenteral formulations for the treatment of adermatological condition (e.g. one or more of rosacea, fungating tumors,and decubitus ulcers).

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may also be used inthe treatment of fungating tumors.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may also be used inthe treatment of decubitus ulcers (bed sores).

In another embodiment, the dermatological condition is caused by one ormore organisms selected from the group consisting of biofilms ofBacillus oleronius, Peptococcus species Bacteroides species, Prevotellaspecies and Peptostreptococcus species.

In another embodiment, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof, are administered topically. For example, (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, or pharmaceutically acceptablesalts or esters thereof, are administered topically for the treatment ofrosacea.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may also be used intreating skin infections (e.g. complicated and uncomplicated skininfections). Specific examples of such skin infections include diabeticfoot ulcers and surgical wound infections which are associated withbiofilms of gram negative anaerobic pathogens and facultative anaerobicpathogens.

The methods of the present invention also include treating Lyme Disease;the method comprising administering to a subject in need thereof atherapeutically effective amount of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof.

Another embodiment of the invention includes therapeutic uses of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, in different oral,topical and parenteral formulations for the treatment of bacterialinfections including Lyme disease (e.g. that caused by Borreliaburgdorferi). (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, may be incombination with one or more antibiotics in the tetracycline, betalactam (penicillin & cephalosporin) and macrolide classes of antibioticswhere there is a likelihood of the presence of the cystic form of thebacteria as well as other forms highly sensitive to these other classesof drugs.

Another embodiment of the present invention includes a method oftreating both spirochete forms, hard body/cystic forms, and biofilmforms of Lyme Disease; the method comprising administering to a subjectin need thereof a therapeutically effective amount of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, or pharmaceutically acceptablesalts or esters thereof.

In another specific embodiment, the Lyme Disease is caused by Borreliaspirochetes and at least some of the Borrelia spirochetes are present inbiofilm or a hard round body or cystic form. In another specificembodiment, the (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, are administered incombination with a therapeutically effective amount of one or moreantibiotics selected from the group consisting of tetracycline, and orβ-lactam antibiotics, and or macrolide antibiotics. In another specificembodiment, the β-lactam antibiotics are selected from one or more ofthe group consisting of penicillin and cephalosporin. In anotherspecific embodiment, the macrolide antibiotics are selected from one ormore of the group consisting of erythromycin, clarithromycin, andazithromycin. The tetracycline antibiotic may be doxycycline.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may also be usedfor treating Lyme Disease. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole may be for use in treating infections caused byBorrelia spirochete bacteria e.g. one or more of Borrelia burgdorferisensu lato (which includes the three genospecies Borrelia burgdorferisensu strict, Borrelia garinii, and Borrelia afzelii). Such bacteriacause a range of infections including Lyme Disease. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole are particularly useful in treatinginfections (e.g. Lyme Disease) caused by Borrelia in biofilms and in ahard body or cystic form, something that many other classes ofantibiotic drugs cannot do. The biofilm and cystic form results in avery long latent stage of Lyme Disease and a reduction or elimination ofsuch forms would be expected to be beneficial in the treatment of thedisease.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole combinationproducts are particularly effective in treating Lyme Disease which is ina mixed form, e.g. Lyme disease in which the spirochetes are present ineither a biofilm or a cystic form and in another form (e.g. a corkscrewform). Thus, compositions of the invention may be used to treatinstances of Lyme disease in which at least some of the spirochetes arepresent in a cystic form or biofilm form.

In a particular embodiment, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are used to treat joint infections associated with LymeDisease, for example infection of the synovial tissue and joint fluid.As such the treatment of Lyme disease with (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole may be effecting in treating oralleviating symptoms of some of the clinical manifestations of Lymedisease such as Lyme arthritis, resulting in reduction or eliminationof, for example, joint and/or muscle pain or joint swelling associatedwith the infection.

The methods of the present invention also include treating a disease,the method comprising administering to a subject in need thereof atherapeutically effective amount of (R)- or (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole nidazole, or pharmaceuticallyacceptable salts or esters thereof; wherein the disease is selected fromone or more diseases selected from the group consisting of Glanders andMelioidosis infections.

In another embodiment, the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof, are used to treat the Glanders or Melioidosis infections arecaused by biofilms of Burkholderia mallei or Burholderia pseudomalleiand at least some of the bacteria are present in an aneroebicconfiguration.

In another embodiment, the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof, that are used to treat the Glanders or Melioidosis infectionscaused by biofilms Burkholderia mallei or Burholderia pseudomallei areused in combination with one or more antibiotics, the antibiotics beingselected from β-lactam antibiotics, tetracycline antibiotics, penemantibiotics, quinolone antibiotics and macrolide antibiotics. Theseantibiotics will be active against the bacteria while it is in anaerobic format for its respiration while (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole will be active against the bacteria while they arein an anaerobic format for their respiration.

The methods of the present invention also include treating a disease,the method comprising administering to a subject in need thereof atherapeutically effective amount of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof; wherein the disease is Q-fever.

In another embodiment, the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof, are used to treat the Q fever infection caused by Coxiellaburnetii, a bacterium that affects humans and other animals, and atleast some of the bacteria are a spore-like small cell variant, and areobligate intracellular pathogens.

In another embodiment, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof, that is used to treat Q-fever is for use in combination withone or more antibiotics, the antibiotics being selected from β-lactamantibiotics, tetracycline antibiotics, penem antibiotics, quinoloneantibiotics and macrolide antibiotics that can contribute to the killingof the Coxiell burnetti bacteria that take sanctuary in the highlyacidic vacuoles of the human host's macrophages in the gastrointestinaltrack.

The methods of the present invention also include treating a disease,the method comprising administering to a subject in need thereof atherapeutically effective amount of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof; wherein the disease is selected from one or more diseasesselected from the group consisting of systemic and cardiovascularinfections, bone and joint infections, CNS infections, upper and lowerrespiratory infections and lung infections. In a specific embodiment,the disease is selected from: septicemia, septic shock, bacteremia,endocarditis, indwelling catheter or device infections, osteomyelitis,joint infection, septic arthritis, meningitis, encephalitis, brainabscess, sinusitis, tonsillitis, lung abscess, emphysema, pneumonia,(including noscomial, aspiration and community acquired pneumonia),bronchitis. In another specific embodiment, the disease is caused by oneor more organisms selected from the group consisting of morphologicalforms, including biofilms, of Prevotella species, Peptococcus species,Bacteroides species, Clostridium species and Peptostreptococcus species.

Another embodiment of the invention includes a method of treating adisease, the method comprising administering to a subject in needthereof a therapeutically effective amount of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, or pharmaceutically acceptablesalts or esters thereof; wherein the disease is selected from: systemicand cardiovascular infections, bone and joint infections, CNSinfections, upper and lower respiratory Infections and lung infections.

In another specific embodiment, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof, is administered in combination with a therapeutically effectiveamount of one or more other antibiotics for cardiovascular infections,bone and joint infections, CNS infections, upper and lower respiratoryinfections and lung infections. In another specific embodiment, the oneor more other antibiotics are selected from tetracycline antibiotics,macrolide antibiotics, quinolone antibiotics, β-lactam antibiotics andpenem antibiotics.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolemay also be used in treating heart infections. A specific example ofsuch cardiac infections is endocarditis.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolemay also be used in treating central nervous system infections. Specificexamples of such central nervous system infections include meningitis,brain abscesses, and a bacterial dysbiosis that exacerbate the symptomsof autism and Parkinson's disease.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolemay also be used in treating blood infections. Specific examples of suchblood stream infections include bacteremia and septicemia.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolemay also be used in treating bone and joint infections.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolemay also be used in treating lung infections. Specific examples of suchpulmonary infections include one or more of emphysema, pneumonia &aspiration pneumonia, Lemmiere's Syndrome, and lung abscess.

Another embodiment of the invention includes a method of preventing thetransmission of a sexually transmitted disease; the method comprisingadministering to a subject in need thereof a therapeutically effectiveamount of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, or apharmaceutically acceptable salt or ester thereof.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolemay be used for the reduction of incidence and prevention of sexuallytransmitted diseases and this transmission related to bacterialvaginosis and/or trichmoniasis and/or vaginal candidiasis. Exemplarysexually transmitted diseases the transmission of which can be preventedaccording to this invention include human immunodeficiency virus (HIV),herpes simplex virus (HSV), hepatitis C virus (HCV), hepatitis B virus(HBV), human papilloma virus (HPV), gonorrhea, and syphilis, includingYaws, a skin contact transmitted spirochete disease. Bacterialvaginosis, often caused by biofilms of Gardnerella vaginalis, andrelated infections are known to increase the likelihood of STDtransmission to women suffering from the infection and from the women totheir sexual partners. In particular, (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole have excellent activity against Gardnerellavaginalis. Thus, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolemay be used to prevent the transmission of sexually transmitted diseasesto women and to men.

The methods of the present invention include inhibiting or reducing theincidence of the transmission of a sexually transmitted disease; themethod comprising administering to a subject in need thereof atherapeutically effective amount of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof.

Another embodiment of the invention includes a method of treating asexually transmitted disease; the method comprising administering to asubject in need thereof a therapeutically effective amount of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof.

In a specific embodiment, the disease that may be treated by(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may be one or morediseases selected from the group consisting of biofilms of syphilis,yaws (transmitted by non-sexual contact), and bacterial urethritis inmen or women.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolemay also be used in treating bacterial urethritis, particularly in men,but also in women. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare highly active against biofilms of Gardnerella vaginosis, Bacteroidesspecies, Prevotella species and Mobiluncus species that are causativepathogens in bacterial urethritis. In particular, (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole have excellent activity againstbiofilms of Gardnerella vaginalis, Atopobium, Bacteroides species andPrevotella species. The infection of women with bacterial urethritis andthe recurrence of bacterial vaginosis is often attributed totransmission of the infection from their male sexual partner withbacterial urethritis. Typically, the woman's male sexual partner wouldhave contracted the infection (in the man it takes the form of bacterialurethritis or similar) from a woman, possibly is regular female sexualpartner or possible from a different partner. Bacterial urethritis isoften asymptomatic in men. Thus, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole may be used in either the treatment or the prophylaxisof bacterial urethritis and the prophylaxis of vaginosis, byadministering (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in atherapeutically effective dose to a subject's sexual partner. Of course,typically the treatment and the prophylaxis of bacterial vaginosis willbe conducted simultaneously by administering to a subject and to asubject's sexual partner a therapeutically effective amount of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole. Thus, the(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may be used in thetreatment or prophylaxis of bacterial urethritis, particularly in menwho are the sexual partners of women suffering from bacterial urethritisor bacterial vaginosis. Prophylactic treatment of a male sexual partnerof an infected woman may be beneficial in preventing or reducing therisk of transmission of infection to the male partner.

In a specific embodiment, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole may used in men in a single 1.5 gram dose for thetreatment and prophylaxis of bacterial urethritis and the prophylaxis ofbacterial urethritis and bacterial vaginosis in the male's female sexualpartner. Since the infection is men is asymptomatic, this single doseregimen will gain far greater compliance/adherence than in multiple doseregimens and will thus be more effective in treating infection andpreventing transmission to new partners.

Another embodiment of the invention includes a method of treatmentand/or reduction of incidence/prophylaxis of a gynecological,genitourinary or vaginal infection; the method comprising administeringto a subject in need thereof a therapeutically effective amount of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, or apharmaceutically acceptable salt or ester thereof.

In a specific embodiment, the methods include treating and/or reducingthe incidence of a gynecological, genitourinary or vaginal infection;the method comprising administering to a subject in need thereof atherapeutically effective amount of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof. Such infections include one or more of vulvovaginitis,bacterial vaginosis, vaginal candidiasis (yeast infections) (e.g. mixedinfections which include vaginal candiasis), and trichomoniasis.

In another specific embodiment, the gynecological, genitourinary orvaginal infection is selected from one or more infections/diseasesselected from the group consisting of bacterial vaginosis,vulvovaginitis, vaginal candidiasis (yeast infections), bacterialurethritis, protozoal urethritis, sexually transmitted urethritis,cystits, pyleonephritis, prostatitis, urosepsis, urinary tractinfections, trichomoniasis, endometritis, endomyometritis, tubo-ovarianabscess, gynecological infection resulting in premature rupture ofmembrane in pregnancy and pre-term labor (PRM/PTL), pelvic inflammatorydisease (PID) and postsurgical vaginal cuff infection.

Thus, the genitourinary infection may be selected from one or moreinfections/diseases selected from the group consisting of: bacterialvaginosis, bacterial urethritis, prostatitis, urosepsis, urinary tractinfections, endometritis, endomyometritis, tubo-ovarian abscess,gynecological infection resulting in premature rupture of membrane inpregnancy/pre-term labor (PRM/PTL), pelvic inflammatory disease (PID)and postsurgical vaginal cuff infection. In a further embodiment theinfection is selected from endometritis, endomyometritis, tubo-ovarianabscess, gynecological infection resulting in premature rupture ofmembrane in pregnancy (PRM/PTL) pelvic inflammatory disease (PID) andpostsurgical vaginal cuff infection.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may also be used intreating bacterial vaginosis. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are highly active against biofilms of Gardnerellavaginosis, Bacteroides species, Prevotella species, and Mobiluncusspecies.

In a further specific embodiment the infection is PID. In a furtherembodiment the infection is selected from endometritis, endomyometritis,tubo-ovarian abscess, gynecological infection resulting in prematurerupture of membrane in pregnancy (PRM/PTL) preterm labor, andpostsurgical vaginal cuff infection.

In another specific embodiment, the gynecological, genitourinary orvaginal infection is caused, at least in part, by one or more organismsselected from the group consisting of biofilms of Gardnerella vaginalis,Mobiluncus curtisii, Prevotella species, Bacteroides species, Atopobiumvaginae, Peptococcus species, Peptostreptococcus species, Clostridiumspecies and Trichomonas vaginalis.

In another specific embodiment, the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or esters thereofis administered in combination with a therapeutically effective amountof an anti-fungal drug.

In another specific embodiment, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or esters thereofare administered in combination with a therapeutically effective amountof an antifungal drug.

In another specific embodiment, the co-administered antifungal drug istopically administered to the vagina.

In another specific embodiment, the co-administered antifungal drug isadministered systemically.

In another specific embodiment, the antifungal drug is selected from:azole antifungal drugs, triazole antifungal drugs, thiazole antifungaldrugs and echinocandin antifungal drugs, or a combination thereof. Inanother specific embodiment, the antifungal drug is selected from:fluconazole, miconazole nitrate, clotrimazole, econazole, saperconazole,terconazole, fenticonazole, sertaconazole, posaconazole, itraconazole,ketoconazole, butaconazole, tioconazole, cyclopirox, caspofungin,micafungin, and anidulafungin and their pharmaceutically acceptablesalts, or a combination thereof.

In another specific embodiment of the invention, the methods includeadministering (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutical salts or esters thereof topically to the vagina. Inanother specific embodiment, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutical salts or esters thereof, areadministered systemically.

The methods of the present invention also include treating odontogenic,dental and periodontal infections; the method comprising administeringto a subject in need thereof a therapeutically effective amount of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof.

In a specific embodiment, the infection is selected from: dentalcarries, peri-apical abscess, periodontal abscess, and acuteperi-coronitis of impacted or partially erupted teeth.

In another embodiment, the infection is caused by one or more organismsselected from the group consisting of biofilms of Prevotella species,Peptococcus species, Peptostreptococcus species, Porphryomonas species,Bacteroides species, Clostridium species, Fusobacterium Species,Streptococcus species, Treponema species, Lactobacilli species andActinomyces species.

In another specific embodiment, the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof, are administered in combination with a therapeuticallyeffective amount of one or more other antibiotics. In another specificembodiment, the one or more other antibiotics are selected fromtetracycline antibiotics, macrolide antibiotics, quinolone antibiotics,β-lactam antibiotics and penem antibiotics.

In another embodiment, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole may also be used in treating a specific dental orperiodontal infection, e.g. a disease selected from: dental carries,peri-apical abscess, periodontal abscess, and acute peri-coronitis ofimpacted or partially erupted teeth. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are highly active against biofilms of bacterial speciesincluding Bacteroides fragilis, Fusobacterium species,Peptostreptococcus species, Prevotella species, Pophyromonas species,and Actinomyces species. These bacterial species are commonly associatedwith the above mentioned dental and periodontal infections. Inparticular, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole haveexcellent activity against biofilms of Bacteroides fragilis.

The methods of the present invention include treating a bacterialinfection, the method comprising administering to a subject in needthereof a therapeutically effective amount of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, or pharmaceutically acceptablesalts or esters thereof; wherein the bacterial infection is caused bybiofilms or planktonic morphologies of one or more organisms selectedfrom the group consisting of Helicobacter pylori, Bacteroides fragilis,Bacteroides thetaiotaomicron; Parabacteroidea distasonis, Fusobacteriumgonidiaformans, Fusobacterium nucleatum, Prevotella amnir, Prevotellabivia, Prevotella disiens, Prevotella melaninogenica, Prevotellatimonensis, Porphyromonas asacharlytica, Porphyromonas gingivalis,Porphyromonas uenonis, Megasphaera-1, Megasphaera-2, Gardnerellavaginalis, Mobiluncus curtisii, Mobiluncus mulieris, Actinomycesisraelii, Actinomyces neui ssp. anitratus, Actinomyces neui ssp. neui,Actinomyces odontolyticus, Actinomyces radingae, Actinomyces turicensis,Clostridium difficile, Clostridium innocuom, Clostridium perfringens,Clostridium ramosum, Finegoldia magna, Anaerococcus prevotii,Anaerococcus tatradius, Peptostreptococcus anaerobius, Peptoniphilusasaccharolyticus, Peptoniphilus harei, Peptoniphilus lacrimalis andAtopobium vaginae.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare for use in treating a disease caused by anaerobic bacteria. In analternative embodiment, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are for use in treating a disease caused by aerobicbacteria. In an embodiment, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are for use in treating a disease caused by Gramnegative bacteria, e.g. a resistant strain of Gram negative bacteria. Inan alternative embodiment, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are for use in treating a disease caused by Grampositive bacteria.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare for use in treating a disease selected from resistant H. pyloriinfection, (including, but not limited to, metronidazole resistant H.pylori infection), odontogenic infections, and Lyme Disease.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare for use in treating anaerobic bacterial infections. Such anaerobicbacterial infections include: one or more or urinary tract infections,skin and skin structure infections, abdominal and intra-abdominalinfections, ulcerative colitis, diverticulitis, and endometritis. Theanaerobic bacterial infection may be caused by a Gram negative anaerobe.

Thus, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may be usedin treating urinary tract infections (e.g. complicated and uncomplicatedurinary tract infections).

Other bacterial biofilm infections include: C. Difficile infections,abdominal infections, gastrointestinal infections, dental infections,urinary tract infections, complicated & uncomplicated skin Infections,lung infections, CNS Infections, blood Infections, bone and jointinfections, and heart infections.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare in combination with one or more other actives.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare in combination with a macrolide antibiotic. Exemplary macrolideantibiotics include erythromycin, clarithromycin, & azithromycin.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may be incombination with an anti-inflammatory agent. Thus, in one embodiment acombination of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole anda macrolide antibiotic may be used in combination with ananti-inflammatory agent. Additionally or alternatively (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole may be in combination with a protonpump inhibitor. Thus, a combination of (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole and a macrolide antibiotic may be used incombination with a proton pump inhibitor (and/or an anti-inflammatoryagent). Exemplary anti-inflammatory agents include mesalazine (which maybe in a short or long acting form). Exemplary proton pump inhibitorsinclude omeprazole (e.g. s-omeprazole).

The combination of a proton pump inhibitor and/or an anti-inflammatoryagent with (R)-ornidazole (and/or another antibiotic, e.g. a macrolideantibiotic) is expected to alleviate the symptoms of the infection atthe same time as the (R)-ornidazole treats the cause of the infection.Among other benefits this can result in increased patient compliance.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare used in combination with a quinolone antibiotic, particularly anorally administered quinolone antibiotic. Exemplary quinoloneantibiotics include ciprofloxacin, levofloxacin, enoxacin, fleroxacin, &ofloxacin.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare used in combination with a tetracycline antibiotic, particularly anorally administered tetracycline antibiotic. An exemplary tetracyclineantibiotic is doxycline.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare used in combination with an antifungal drug. Exemplary antifungaldrugs include those which are active against Candida albicans, e.g.azole antifungal drugs, triazole antifungal drugs, thiazole antifungaldrugs and echinocandin antifungal drugs, or a combination thereof, Morespecific antifungal drugs include fluconazole, miconazole nitrate,clotrimazole, econazole, saperconazole, terconazole, fenticonazole,sertaconazole, posaconazole, itraconazole, ketoconazole, butaconazole,tioconazole, cyclopirox, caspofungin, micafungin, and anidulafungin andtheir pharmaceutically acceptable salts, or a combination thereof. Thus,the combination of antibacterial and antiprotozoal (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole with an antifungal drug can preventsecondary super-infections, reduce morbidity and medical expense, andspeed recovery. As these indications can also lead to increase risk ofSTD transmission, eliminating the possibility that any of theseinterrelated indications return is of utility in limiting the spread ofa number of STDs.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare used in combination with a β-lactam antibiotic. Exemplary β-lactamantibiotics include amoxillin, cefazolin, cefuroxime, ceftriaxone,cefipime, ceftazidime, & cefoxitin. Further exemplary β-lactamantibiotics include penicillin, amoxiclav, & cephalosporins.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare used in combination with a penem antibiotic, such as imipenem.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare in a fixed dose combination with the above described antibiotics.

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare in an oral formulation. If the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are in an oral formulation and it is used incombination with one or more other actives, one or more of the otheractives may be in a separate formulation, for example a topicalformulation (e.g. a vaginal topical formulation). Alternatively, the oneor more other actives may be in the same oral formulation as the(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole. In a furtheralternative, the one or more of the other actives are in a differentoral formulation to the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole.

Alternatively, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole maybe in a topical formulation (e.g. a vaginal topical formulation or atopical skin semisolid formulation like a cream). If the (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole are in a topical formulation and itis used in combination with one or more other actives, one or more ofthe other actives may be in an oral formulation. Alternatively, the oneor more other actives may be in the same topical formulation as the(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole. In a furtheralternative, the one or more of the other actives are in a differenttopical formulation to the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole.

Another embodiment of the invention includes a method for theprophylaxis and treatment of diseases, the method comprising treating asubject in need thereof with a therapeutically active amount of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof.

Another embodiment of the invention includes a pharmaceuticalformulation comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof. The formulation may also comprise a pharmaceutically acceptableexcipient (e.g. an adjuvant, diluent or carrier).

Another embodiment of the invention includes a kit comprising apharmaceutical formulation comprising (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof, (and optionally at least one other active agent). The kit mayalso comprise and a separate pharmaceutical formulation comprising atleast one other active agent.

Another embodiment of the invention includes the use of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, or pharmaceutically acceptablesalts or esters thereof, in a fixed dose combination product with amacrolide antibiotic for the prophylaxis and/or treatment of diseasesrelated to biofilms of one or more of H. Pylori Infection (includingmetronidazole resistant H. Pylori infection), odontogenic, dental andperiodontal infections and Lyme Disease (e.g. Lyme disease in which thespirochetes are in their biofilm orcystic form). In this embodiment thefixed dose combination is suitably for the prophylaxis and/or treatmentof a disease related to odontogenic, dental and periodontal infectionsand Lyme Disease (e.g. Lyme disease in which the spirochetes are intheir biofilm or cystic form).

Another embodiment of the invention includes the use of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, or pharmaceutically acceptablesalts or esters thereof, in a fixed dose combination product with aquinolone antibiotic for the prophylaxis and/or treatment of anaerobicbacterial infections (e.g. one or more of complicated and uncomplicatedurinary tract infections, complicated and uncomplicated skin and skinstructure infections, abdominal and intra-abdominal infections, Crohn'sDisease, diverticulitis (for example complicated diverticulitis), pelvicinflammatory disease, and endometritis).

Another embodiment of the invention includes the use of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, or pharmaceutically acceptablesalts or esters thereof, fixed dose drug combinations of oral andtopical vaginal formulations of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole with different oral and vaginal topical formulations ofantifungal drugs (including, but not limited to, fluconazole, miconazolenitrate, clotrimazole, econazole, saperconazole, terconazole,fenticonazole, sertaconazole, posaconazole, itraconazole, ketoconazole,butaconazole, tioconazole, cyclopirox, caspofungin, micafungin, andanidulafungin and their pharmaceutically acceptable salts, orcombination thereof), for the prophylaxis and/or treatment ofgynecological and vaginal infections including bacterial vaginosis,vulvovaginitis, vaginal candidiasis (yeast infections), andtrichomoniasis.

Another embodiment of the invention includes therapeutic uses of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, in different oral,topical and parenteral formulations for the treatment of bacterialinfections including Lyme Disease (e.g. that caused by Borreliaburgdorferi). (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, may be incombination with one or more antibiotics in the tetracycline or betalactam (penicillin & cephalosporin) and macrolide classes of antibioticswhere there is a likelihood of the presence of the cystic form of thebacteria as well as other forms highly sensitive to these other classesor drugs.

Another embodiment of the invention includes therapeutic uses of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, in different oral,topical, and parenteral formulations for the treatment of adermatological condition (e.g. one or more of acne, rosacea, fungatingtumors, and decubitus ulcers).

Another embodiment of the invention includes therapeutic uses of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, in oral, topicaland parenteral formulations for the treatment of bacterial biofilminfections including, but not limited to anaerobic bacterial infections(e.g. one or more of C. Difficile infections, H. Pylori infections,abdominal infections, GI infections, dental infections, urinary tractinfections, skin infections (e.g. complicated & uncomplicated skininfections), lung infections, CNS infections and conditions, bloodinfections, bone & joint infections, and heart infections.

Another embodiment of the present invention includes therapeutic uses of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, in a combinationproduct (e.g. a fixed dose combination product) with a beta lactamantibiotic (including, but not limited to amoxillin, cefazolin,cefuroxime, ceftriaxone, cefipime, ceftazidine, & cefoxitin) for theprophylaxis and/or treatment of diseases related to H. Pylori infection,diverticulitis, gastric, dental, and abdominal and intra-abdominalinfections.

Another embodiment of the present invention includes a method oftreating a disease selected from: H. Pylori Infection, odontogenic,dental and periodontal infections and Lyme Disease; the methodcomprising administering to a subject in need thereof a therapeuticallyeffective amount of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof, in combination with a therapeutically effective amount of amacrolide antibiotic.

Another embodiment of the present invention includes a method oftreating an anaerobic bacterial infection; the method comprisingadministering to a subject in need thereof a therapeutically effectiveamount of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, in combination witha therapeutically effective amount of a quinolone antibiotic.

Another embodiment of the present invention includes a method oftreating a gynecological or vaginal infection; the method comprisingadministering to a subject in need thereof a therapeutically effectiveamount of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, in combination witha therapeutically effective amount of an antifungal drug.

Another embodiment of the present invention includes a method ofpreventing the transmission of a sexually transmitted disease; themethod comprising administering to a subject in need thereof atherapeutically effective amount of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof, in combination with a therapeutically effective amount of anantifungal drug.

Another embodiment of the present invention includes a method oftreating Lyme Disease caused by Borrelia spirochetes and wherein atleast some of the Borrelia spirochetes are present a biofilm or cysticform; the method comprising administering to a subject in need thereof atherapeutically effective amount of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or salts thereof,in combination with a therapeutically effective amount of one or moreantibiotics, the antibiotics being selected from tetracycline, β-lactamantibiotics and macrolide antibiotics.

Another embodiment of the present invention includes a method oftreating a bacterial infection, the method comprising administering to asubject in need thereof a therapeutically effective amount of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof; wherein thebacterial biofilm or planktonic infection is caused by an organismselected from: Bacteroides fragilis, Bacteroides thetaiotaomicron;Parabacteroidea distasonis, Fusobacterium gonidiaformans, Fusobacteriumnucleatum, Prevotella amnii, Prevotella bivia, Prevotella disiens,Prevotella melaninogenica, Prevotella timonensis, Porphyromonasasacharlytica, Porphyromonas gingivalis, Porphyromonas uenonis,Megasphaera-1, Megasphaera-2, Gardnerella vaginalis, Mobiluncuscurtisii, Mobiluncus mulieris, Actinomyces israelii, Actinomyces neuissp. anitratus, Actinomyces neui ssp. neui, Actinomyces odontolyticus,Actinomyces radingae, Actinomyces turicensis, Clostridium difficile,Clostridium innocuom, Clostridium perfringens, Clostridium ramosum,Finegoldia magna, Anaerococcus prevotii, Anaerococcus tatradius,Peptostreptococcus anaerobius, Peptoniphilus asaccharolyticus,Peptoniphilus harei, Peptoniphilus lacrimalis and Atopobium vaginae.

Other embodiments of the present invention include methods ofmanufacturing (R)-ornidazole and (S)-ornidazole. In a specificembodiment, the methods include manufacturing (R)-ornidazole and(S)-ornidazole having an enantiomeric purity of at least about 50%enantiomeric excess (ee), at least about 60% enantiomeric excess (ee),at least about 70% enantiomeric excess (ee), at least about 80%enantiomeric excess (ee), at least about 90% enantiomeric excess (ee),at least about 95% enantiomeric excess (ee), at least about 96%enantiomeric excess (ee), at least about 97% enantiomeric excess (ee),at least about 98% enantiomeric excess (ee), or at least about 99%enantiomeric excess (ee).

In a specific embodiment, the methods of manufacturing (R)-ornidazoleand (S)-ordnidazole include reacting 2-methyl-4(5)-nitroimidazole with(S)-propylene oxide. In a specific embodiment, the reaction is performedin the presence of a Lewis acid. In another specific embodiment, theLewis acid is ZnCl₂. In another specific embodiment, the reaction isperformed in the presence of a Bronsted acid. In another embodiment, theBronsted acid is formic acid. It may be that performing the reaction inthe presence of a Lewis Acid rather than a Bronsted acid providesincreased reproducibility (e.g. of yield, enantiomeric excess,regioisomeric purity etc.). The present invention also includes thecompound (R)-ornidazole having an enantomeric purity of at least about95% ee, prepared by a process comprising the step of reacting2-methyl-4(5)-nitroimidazole with (S)-propylene oxide. The presentinvention also includes the compound (R)-ornidazole having anenantomeric purity of at least about 96% ee, prepared by a processcomprising the step of reacting 2-methyl-4(5)-nitroimidazole with(S)-propylene oxide. The present invention also includes the compound(R)-ornidazole having an enantomeric purity of at least about 97% ee,prepared by a process comprising the step of reacting2-methyl-4(5)-nitroimidazole with (S)-propylene oxide. The presentinvention also includes the compounds (R)-ornidazole and (S)-ornidazolehaving an enantomeric purity of at least about 98% ee, prepared by aprocess comprising the step of reacting 2-methyl-4(5)-nitroimidazolewith (S)-propylene oxide. The present invention also includes thecompound (R)-ornidazole having an enantomeric purity of at least about99% ee, prepared by a process comprising the step of reacting2-methyl-4(5)-nitroimidazole with (S)-propylene oxide.

Another embodiment of the invention includes a method of manufacturing(R)-ornidazole and (S)-ornidazole; the method comprising reacting2-methyl-4(5)-nitroimidazole with (S)-propylene oxide.

In an embodiment, the reaction is performed in the presence of a Lewisacid. In a further embodiment, the Lewis acid is ZnCl₂.

In an alternative embodiment, the reaction is performed in the presenceof a Bronsted acid. In a further embodiment, the reaction is performedin the presence of formic acid. In some embodiments, the acid may alsobe the reaction solvent.

In an embodiment, the reaction is conducted in an ether solvent (e.g.diethyl ether, THF, ^(t)BuOMe). In a further embodiment, the reaction isconducted in THF. This embodiment applies particularly to embodiments inwhich the reaction is conducted in the presence of a Lewis acid.

In an embodiment, the reaction was conducted at a reduced temperature.In a further embodiment, the reaction was conducted at a temperature ofabout 10° C. In an embodiment, the reaction was conducted at atemperature from about 0 to about 25° C. Thus, the reaction wasconducted at a temperature from about 5 to about 15° C. Specifically,the reaction was conducted at a temperature from about 7 to about 13° C.

This is a more efficient process than the one previous enantioselectivesynthesis of Ornidazole enantiomers (CN 101108828) which requirespre-activation of 2-methyl-4(5)-nitroimidazole before reaction with thechiral side chain precursor. On the other hand, the present inventionprovides a one-step, one-pot enantioselective synthesis of(R)-ornidazole or (S)-ornidazole. In some embodiments, due to themethods of manufacturing, the (R)-ornidazole and (S)-ornidazole, or apharmaceutically acceptable salts or esters thereof, have anenantiomeric purity of at least about 50% enantiomeric excess (ee), atleast about 60% enantiomeric excess (ee), at least about 70%enantiomeric excess (ee), at least about 80% enantiomeric excess (ee),at least about 90% enantiomeric excess (ee), at least about 95%enantiomeric excess (ee), at least about 96% enantiomeric excess (ee),at least about 97% enantiomeric excess (ee), at least about 98%enantiomeric excess (ee), or at least about 99% enantiomeric excess(ee).

Any of the embodiments described above for the first aspect of theinvention may equally apply to any of the subsequent aspects of theinvention. In addition, any embodiment may also apply to any otherembodiments. In other words, the features described in the aboveembodiments of the invention can be combined.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the invention are further described hereinafter withreference to the accompanying drawings, FIG. 1, in whichstereo-selective syntheses are described.

DETAILED DESCRIPTION OF THE INVENTION

All publications, patents and patent applications, including anydrawings and appendices therein are incorporated by reference in theirentirety for all purposes to the same extent as if each individualpublication, patent or patent application, drawing, or appendix wasspecifically and individually indicated to be incorporated by referencein its entirety for all purposes.

In any aspect or embodiment of the invention described in thisspecification, the (R)-ornidazole may be in the form of apharmaceutically acceptable salt (e.g. the HCl salt) or ester.Alternatively, the (R)-ornidazole may be present as a free base, i.e.not in the form of a salt. The (R)-ornidazole, or pharmaceuticallyactive salt or ester thereof, may be in the form of a hydrate.

Likewise, many of the embodiments of the invention are concerned withcombinations of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolewith one or more other active agents. Where appropriate, andirrespective of whether (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are in the form of a pharmaceutically acceptable salts,any one or more of the other active agents may be in the form of apharmaceutically acceptable salt.

Suitable pharmaceutically acceptable salts include, but are not limitedto, salts of pharmaceutically acceptable inorganic acids such ashydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic,and hydrobromic acids, or salts of pharmaceutically acceptable organicacids such as acetic, propionic, butyric, tartaric, maleic,hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic,succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic,benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic,stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic andvaleric acids.

It is intended that the aspects and embodiments of this inventionencompasses (R)-ornidazole and/or any other active agent in all solidforms, including amorphous forms, as well as crystalline forms, andpolymorphs thereof.

By (S) enantiomer is intended to mean that enantiomer which produces apositive optical rotation. This has been shown, through independentsynthesis, to be the (S)-enantiomer and is identified as such throughoutthis specification. In the unlikely event that this assignment has beendone in error, this specification is directed to (+)-Ornidazole.

This invention relates to various uses and syntheses of (R)-ornidazole.In this context (R)-ornidazole is not intended to refer only to pure(S)(+)-Ornidazole but also to Ornidazole in which the (S)(+)-enantiomerpredominates over the (R)(−)-enantiomer. Thus, the term(S)(+)-senidazole also includes mixtures in which there is a smallamount (e.g. less than 10% by weight, e.g. less than 5% by weight) of(R)(−)-Ornidazole.

The term “(S)(+)-senidazole” thus includes (S)(+)-Ornidazole by itselfor when it is available in an enantiomeric excess over the(R)(−)-Ornidazole enantiomer.

Macrolide antibiotics are antibiotics which comprise a large (e.g. 14-,15- or 16-membered) macrocyclic lactone ring. Exemplary macrolideantibiotics include: dirithromycin, roxithromycin, telithromycin,erythromycin, clarithromycin, & azithromycin and in particularerythromycin, clarithromycin, & azithromycin.

β-Lactam antibiotics are antibiotics in which the structure features af-lactam moiety. They include cefalosporins (e.g. corecefazolin,cefacetrile, cefaloglycin, cefalonium, cefaloridine, cefalotin,cefapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine,ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide,cefotiam, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan,cefmetazole, flomoxef, loracarbef, cefixime, ceftazidime, ceftriaxone,cefcapene, cefdaloxime, cefetamet, cefmenoxime, cefodizime,cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime,cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, latamoxef,cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline,cefdinir, cefprozil, cefalexin), penems (e.g. faropenem, biapenem,doripenem, ertapenem, imipenem, meropenem, panipenem) and penicillinderivatives (e.g. amoxillin and penicillin). Exemplary β-lactamantibiotics include amoxillin, amoxiclav, cefazolin, cefuroxime,ceftriaxone, cefipime, ceftazidine, & cefoxitin. Further exemplaryβ-lactam antibiotics include penicillin & cephalosporin.

Quinolone antibiotics (which include the fluoroquinolone antibiotics)are antibiotics with a quinolone (or aza-quinolone) backbone. Theyinclude enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin,rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin,temafloxacin, tosufloxacin, besifloxacin, clinafloxacin, garenoxacin,gemifloxacin, gatifloxacin, sitafloxacin, trovafloxacin, prulifloxacin,ciprofloxacin, levofloxacin and ofloxacin. Exemplary quinoloneantibiotics include ciprofloxacin, levofloxacin, enoxacin, fleroxacin, &ofloxacin.

Where antibiotics (and particularly quinolone antibiotics) are used incombination with (R)-ornidazole, the antibiotic will typically beadministered orally.

Proton pump inhibitors slow the production of gastric acid. Examplesinclude omeprazole, lansoprazole, dexlansoprazole, esomeprazole,pantoprazole, rabeprazole, ilaprazole. A particular proton pumpinhibitor suitable for use in the combinations of the invention isomeprazole (e.g. s-omeprazole).

Antiinflammatory agents may be steroidal (e.g. corticoids) ornon-steroidal (e.g. aspirin, ibuprofen, mesalazine). An particularanti-inflammatory agent suitable for use in the combinations of theinvention is mesalazine. Antifungal agents suitable for use in thecombinations of the invention include: fluconazole, miconazole nitrate,clotrimazole, econazole, saperconazole, terconazole, fenticonazole,sertaconazole, posaconazole, itraconazole, ketoconazole, butaconazole,tioconazole, cyclopirox, caspofungin, micafungin, and anidulafungin.

Throughout this specification, the terms aerobic and anaerobic bacteriaare used to describe the bacterial species against which (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole are active against. Bacterialspecies may be obligate aerobic species or they may be non-obligateaerobic species. Likewise, bacterial species can be obligate anaerobicspecies or non-obligate species. Sometimes, an obligate aerobic speciesis able to survive in anaerobic conditions by the actions ofaccompanying anaerobic bacteria. (R)-ornidazole is useful againstbiofilm infections caused by any or all of the above bacteria.

Throughout this specification the term ‘in combination’ means thateither (R)-ornidazole, (S)-ornidazole, or (rac)-ornidazole and the oneor more other actives are both administered to the patient over the sameperiod of treatment. They may be administered together, i.e. at the sametime. In this case they may be administered in a single formulation,(e.g. as a single tablet or capsule or sachet) or in separateformulations administered simultaneously or nearly simultaneously.Alternatively, they may be administered at separate times of day. Wherethe (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole and otheractive(s) are administered separately it is to be under stood that thetiming of separate dosing is selected such that the beneficial effect ofthe first administered agent is not lost prior to administration of thesecond or further agent. Whatever the precise timing of theadministration, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole andthe one or more other actives may be administered via different means,e.g. the (R)-ornidazole may be administered in an oral formulation andthe other active may be administered as a topical formulation or viceversa.

The combinations of the invention provide benefits which are at leastadditive compared to the use of either agent alone. In many embodiments,the combinations are something more than additive e.g. synergisticcompared to the use of either agent alone.

References to kits in this specification where (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, or pharmaceutically acceptablesalts or esters thereof, is used in kit form with one or more differentactive agents optionally further comprise instructions for theadministration of the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, or pharmaceutically acceptable salts or estersthereof, and the other active agent(s) in the kit.

The definition of the term ‘treatment’ in this specification encompassesprophylaxis and prevention (i.e. reducing or eliminating the risk ofcontracting the disease). As well as meaning curing a person of thedisease, ‘treatment’ also includes preventing the onset of symptoms,controlling (e.g. by slowing or eliminating) progression of disease,preventing the spread of the disease to other parts of the body and/orto other persons, reducing the spread of the disease and other facets ofmedical practice which will be readily understood by the person skilledin the art to fall within the meaning of the term ‘treatment’.

Throughout the description and claims of this specification, the words“comprise” and “contain” and variations of them mean “including but notlimited to”, and they are not intended to (and do not) exclude othermoieties, additives, components, integers or steps. Throughout thedescription and claims of this specification, the singular encompassesthe plural unless the context otherwise requires. In particular, wherethe indefinite article is used, the specification is to be understood ascontemplating plurality as well as singularity, unless the contextrequires otherwise.

Formulations

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. For example, if the(R)-ornidazole is administered orally, then the daily dosage of thecompound of the invention may be in the range from 0.01 micrograms perkilogram body weight (μg/kg) to 100 milligrams per kilogram body weight(mg/kg). In a specific embodiment, the formulations for administrationto a subject contain about 2.0 g of (R)-ornidazole, about 1.5 g of(R)-ornidazole, about 1 g of (R)-ornidazole, about 0.5 g of(R)-ornidazole, about 0.4 g of (R)-ornidazole. 0.3 g of (R)-ornidazole,0.2 g of (R)-ornidazole, and about 0.1 g of (R)-ornidazole. This is alsotrue of the (S) enantiomer of Ornidazole [(S)-ornidazole] and theOrnidazole racemic mixture.

The beneficial properties of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole include a favorable pharmacokinetic and pharmacodynamicprofile. (R)-ornidazole and (S)-ornidazole are components ofrac-ornidazole and have similar, but slightly improved PK profiles.Indeed, In particular embodiments, after administration ofrac-Ornidazole in a formulation, the T_(max) of rac-Ornidazole rangesabout 2 hours to about 4 hours inclusive of all ranges therebetween.

In another embodiment, after administration of rac-ornidazole in aformulation, the C_(max) of rac-ornidazole ranges (after singleadministration) from about 9 mg/L to about 31.5 mg/L, inclusive of allranges therebetween.

In another specific embodiment, rac-ornidazole concentrations, includingthe (R)-ornidazole and (S)-ornidazole components, have been measured inthe colonic (8.7 mg/g) and abdominal (3.6 to 4.4 mg/g) walls andepiploic fat (3.4 to 4.7 mg/g) throughout colorectal surgery in thosereceiving a 1 g intravenous dose for surgical prophylaxis. In anotherstudy, concentrations were measured in epiploic fat (2.48 to 4.64 mg/g)throughout liver transplantation after a 500 mg intravenous dose wasgiven together with ceftriaxone 1 g for surgical prophylaxis.Penetration rates for this study compared with plasma concentrationsranges between 50 and 70%.

In another embodiment, after a single administration of rac-ornidazolein a formulation, the present invention provides an AUC_(0-∞) forrac-ornidazole of about 185 to about 375 mg-hr/L, and about 500 to about511 mg-hr/L, inclusive of all ranges there between. The AUC for the(R)-ornidazole and (S)-ornidazole components are similar.

In another embodiment, after a single administration of rac-ornidazolein a formulation, the elimination half-life (T_(1/2)) of rac-ornidazoleis about 14 hours to about 18 hours. The (T_(1/2)) of the (R)-ornidazoleand (S)-ornidazole components are similar.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, may be used ontheir own but will generally be administered in the form of apharmaceutical composition in which the (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole, or pharmaceutically acceptable salts thereof, arein association with a pharmaceutically acceptable adjuvant, diluent orcarrier. Conventional procedures for the selection and preparation ofsuitable pharmaceutical formulations are described in, for example,“Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton,Churchill Livingstone, 1988.

Depending on the mode of administration of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, the pharmaceutical compositionwhich is used to administer (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole will preferably comprise from 0.05 to 99% w (percent byweight) (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, morepreferably from 0.05 to 80% w (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, still more preferably from 0.10 to 70% w(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, and even morepreferably from 0.10 to 50% w (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, of active ingredient, all percentages by weight beingbased on total composition.

In many of the embodiments of the invention, (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole are used in combination with otheractive agents (e.g. antibiotics, antifungal, anti-inflammatory agent,proton pump inhibitors etc.). Depending on the mode of administration ofthe other active agent, the pharmaceutical composition used toadminister the other active agent (which may or may not be the samepharmaceutical composition which is used to administer (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole will preferably comprise from 0.05to 99% w (percent by weight) of the other active agent, more preferablyfrom 0.05 to 80% w of the other active agent, still more preferably from0.10 to 70% w of the other active agent, and even more preferably from0.10 to 50% w of the other active agent, of active ingredient, allpercentages by weight being based on total composition.

The pharmaceutical compositions may be administered topically (e.g. tothe vagina) in the form, e.g., of creams, gels, lotions, solutions,suspensions, or systemically, e.g. by oral administration in the form oftablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of a sterile solution, suspension or emulsionfor injection (including intravenous, subcutaneous, intramuscular,intravascular or infusion); or by rectal administration in the form ofsuppositories.

For oral administration (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole and/or one or more other active agents may be admixedwith an adjuvant or a carrier, for example, lactose, saccharose,sorbitol, mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum and titanium dioxide. Alternatively, the tablet may becoated with a suitable polymer dissolved in a readily volatile organicsolvent.

For the preparation of soft gelatine capsules, (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole and/or one or more other activeagents may be admixed with, for example, a vegetable oil or polyethyleneglycol. Hard gelatine capsules may contain granules of the compoundusing either the above-mentioned excipients for tablets. Also liquid orsemisolid formulations of the compound of the invention may be filledinto hard gelatine capsules. Liquid preparations for oral applicationmay be in the form of syrups or suspensions, for example, solutionscontaining the compound of the invention, the balance being sugar and amixture of ethanol, water, glycerol and propylene glycol. Optionallysuch liquid preparations may contain colouring agents, flavouringagents, sweetening agents (such as saccharine), preservative agentsand/or carboxymethylcellulose as a thickening agent or other excipientsknown to those skilled in art.

For intravenous (parenteral) administration (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole and/or one or more other activeagents may be administered as a sterile aqueous or oily solution.Parenteral formulations are particularly suitable for patients sufferingfrom a severe infections. The person skilled in the art would be wellaware of what differentiates a serious infection from a non-seriousinfection. By way of example, severe infections include those whichrender the patient unable to take (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole orally, e.g. infections which render the patientunconscious, emetic, weak, delirious etc. The HCl salt of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are particularlysuitable for parenteral administration, e.g. for the treatment of severeinfections.

The size of the dose for therapeutic or prophylactic purposes of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole and/or one or moreother active agents will naturally vary according to the nature andseverity of the conditions, the age and sex of the animal or patient andthe route of administration, according to well known principles ofmedicine.

Dosage levels, dose frequency, and treatment durations of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are expected todiffer depending on the formulation and clinical indication, age, andco-morbid medical conditions of the patient. In adult patients, as asingle agent monotherapy, the daily dose of orally, parentally orrectally administered forms of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are expected to vary from 0.25 g/day-8.0 g/day.Downward dose adjustments from these levels are likely to be needed ininfants (0-2 years of age), children (2-18 years of age), and elderlypatients (greater than 65 years of age), as well as individuals withrenal or liver disease, and upward dose adjustments may be necessary inobese individuals. In adult patients, as a single agent monotherapy, theconcentration of topically or vaginally administered forms of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are expected tovary from 0.10-4.0 g/day with the concentration of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole in the emollient varying between0.25%-5%. As a single agent monotherapy, the standard duration of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole treatment isexpected to vary between one and seven days for most clinicalindications. It may be necessary to extend the duration of treatmentbeyond seven days in instances of recurrent infections or infectionsassociated with tissues or implanted materials to which there is poorblood supply including bones/joints, respiratory tract, endocardium, anddental tissues.

When (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole is combinedwith other medications in fixed dose combinations treatments, the dailydose of orally, parentally, topically, vaginally, or rectallyadministered forms of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are expected to vary from 0.001 g/day-4.0 g/day.

A specific example of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole oral sachet formulations contains (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole and the following excipients: sugarspheres, Povidone, Polyethylene glycol 4000, Aerosil 200, Talc andEudragit NE30D. The formulation weighs 4.2 g and contains 2 g of(R)-ornidazole, i.e. the formulation contains about 48% (R)-ornidazoleby weight.

Treatment of Gastrointestinal Diseases

In an embodiment, (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolemay also be used in treating gastrointestinal infections.

In an embodiment, the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are for use in treating a condition selected fromgastric, dental, abdominal and intra-abdominal infections.

In an embodiment, the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are for use in treating a condition selected fromgastric, dental, abdominal and intra-abdominal infections

Treatment of C. difficile Infections

In one group of embodiments, are provided formulations (e.g. oral orparenteral formulations) comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, alone or in combination with other antibioticsincluding, but not limited to, those in the tetracycline, quinolone,beta lactam, and macrolide classes, for use in treating biofilms oftoxigenic C. difficile infections.

C. difficile causes as many as 3 million cases of diarrhea and colitisper year. Some result in life threatening cases of pseudomebraneouscolitis. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are activeagainst toxigenic Clostridium difficile bacterial infections which causeclinically relevant cases of Clostridium difficile colitis, infectiousdiarrhea, colitis, mucous colitis, and pseudomembranous colitis.(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole can therefore beused as an antibiotic to treat these infections and their diarrheasymptoms either alone or in combination with other antibiotics that areactive against Clostridium difficile bacteria.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment of Clostridium difficile bacterial infectionsand their related indications. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole is rapidly absorbed after oral administration and has alonger terminal elimination half-life (approximately 14-18 hours) thancommonly used drugs in the imidazole class. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole have an elimination half life thatenables more convenient dosing of oral formulations for theseClostridium difficile bacterial infections including sachet formulationsof powder and or pelletized granules, capsules containing the(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, oral solid tabletformulations, parenteral, and liquid oral suspension formulations. Theseinclude sustained release capsule and tablet and sachet formulationswith vehicles for varying absorbencies for delivery to differentlocations in the gastro-intestinal (GI) tract, capsules containingpowders or pelletized granules with these properties, and oral solidtablet formulations with different types of slow release properties.These formulations are particularly appropriate for treatment of gramnegative anaerobic bacteria like Clostridium difficile that are residentin the GI tract which is the typical site of infection. In some case,parenteral formulations, such as (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole in hydrochloride form, are most appropriate forpatients in certain clinical situations where oral formulation deliveryis not feasible or advisable. The disposition of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole in the human body is similar forboth oral and intravenous dosage forms and the present invention appliesto the usage of both of these forms in these settings. Additionallytopical formulations for skin, dental, and vaginal/urinary tractinfections may be appropriate for treatment of infections with thesebacteria in those settings and are included in the present invention.

Treatment of Ulcerative Colitis

In one group of embodiments, is provided the use of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole in a combination product (e.g. afixed dose combination product) with a beta lactam antibiotic for theprophylaxis and treatment of ulcerative colitis.

((R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst biofilms of Helicobacter pylori, Bacteroides species,Fusobacterium species, Clostridium species, Peptococcus species,Peptostreptococcus species, Eubacterium species, and Prevotella species,some of the bacteria which can contribute to causing clinically relevantcases of ulcerative colitis, and beta lactam antibiotics are activeagainst other causative species of bacteria in ulcerative colitis. Thus,combination product of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole and such other antibiotic(s) is expected to havesuperior efficacy in the treatment of these indications compared to theuse of these agents alone. The combination product can be used as afixed dose therapeutic in oral sachet, oral solid, and parentalformulations.

Treatment of Crohn's Disease

In one group of embodiments, is provided the use of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole in a combination product (e.g. afixed dose combination product) with a beta lactam antibiotic for theprophylaxis and treatment of Crohn's Disease.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst biofilms of Helicobacter pylori, Bacteroides species,Fusobacterium species, Clostridium species, Peptococcus species,Peptostreptococcus species, Eubacterium species, and Prevotella species,some of the bacteria which can contribute to causing clinically relevantcases of Crohn's Disease, and beta lactam antibiotics are active againstother causative species of bacteria in Crohn's Disease Thus, combinationproduct of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole and suchother antibiotic(s) are expected to have superior efficacy in thetreatment of these indications compared to the use of these agentsalone. The combination product can be used as a fixed dose therapeuticin oral sachet, oral solid, and parental formulations.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make it appropriate to use them inthe setting of the treatment the above enumerated bacterial infectionsand their related indications. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are rapidly absorbed after oral administration and hasa longer terminal elimination half-life (approximately 14-18 hours) thancommonly used drugs in the imidazole class. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole have an improved elimination halflife that enables more convenient dosing of fixed dose oral formulationsfor these bacterial infections including sachet formulations of powderand or pelletized granules, capsules containing (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, oral solid tablet formulations,and liquid oral suspension formulations. These include oral sachet, andoral solid tablet formulations with different types of slow releaseproperties.

Treatment of Giardiasis and Amoebiasis

In one group of embodiments, is provided the use of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole (e.g. as an oral or parenteralformulation) for the treatment of protozoa infections including, but notlimited to, giardiasis and amoebiasis (e.g. that caused by Entamoebahistolytica and other species).

Giardia lamblia is a flagellated protozoan parasite that colonizes andreproduces in the small intestine, causing giardiasis. The giardiaparasite attaches to the epithelium by a ventral adhesive disc, andreproduces via binary fission. Giardiasis does not spread via thebloodstream, nor does it spread to other parts of the gastro-intestinaltract, but remains confined to the lumen of the small intestine. Giardiatrophozoites absorb their nutrients from the lumen of the smallintestine, and are anaerobes. The present invention includes a varietyof oral and parenteral formulations of the (R) enantiomer of Ornidazolefor the treatment of giardia, including, but not limited to, pelletizedpowder sachets, capsules, tablets, and IV prefilled syringes.

Amoebiasis refers to infection caused by the amoeba Entamoebahistolytica. A gastrointestinal infection that may or may not besymptomatic and can remain latent in an infected person for severalyears, amoebiasis is estimated to cause 70,000 deaths per yearworldwide. Symptoms can range from mild diarrhea to dysentery with bloodand mucus in the stool. E. histolytica is usually a commensal organism.The present invention, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole includes a variety of oral and parenteral formulationsof (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole for thetreatment of amoebiasis, including, but not limited to, pelletizedpowder sachets, capsules, tablets, and IV prefilled syringes.

In addition, the pharmacologic parameters of the (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment of protozoal infections and their relatedindications. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole arerapidly absorbed after oral administration and has a longer terminalelimination half-life (approximately 14-18 hours) than commonly useddrugs in the imidazole class. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole have an improved elimination half life that enablesmore convenient dosing of oral formulations including systemic sachetformulations of powder and or pelletized granules, capsules containing(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, oral solid tabletformulations, and liquid oral suspension formulations. These includesachet formulations with vehicles for varying absorbencies for deliveryto different locations in the gastro-intestinal (GI) tract, capsulescontaining powders or pelletized granules with these properties, andoral solid tablet formulations with different types of slow releaseproperties. These formulations are particularly appropriate fortreatment of protozoal species. The beneficial properties of(R)-ornidazole and (S)-ornidazole also include pharmacokinetic andpharmacodynamic benefits related to product dosing verses the racemicmixture of Ornidazole. These benefits will allow formulations utilizingless drug than the racemic mixture so that patients can ingest smallertablets, capsules, and sachets in some cases, or be able to utilize moreconvenient dosing schedules of forms, including parenteral formulations,that contain the same amount of drug.

Treatment of Diseases Related to Chronic Gastritis

In one group of embodiments, the present invention provides therapeuticuses of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in acombination product (e.g. a fixed dose combination product) with amacrolide (including, but not limited to erythromycin, clarithromycin, &azithromycin) antibiotic for the prophylaxis and treatment of diseasesrelated to H. Pylori biofilm infection, (including metronidazoleresistant H. Pylori infection), including, but not limited to chronicgastritis and gastric cancer. Additional embodiments of this fixed dosecombination product would also include a proton pump inhibitor (e.g.omeprazole) and or an antiinflammatory agent (e.g. Mesalamine, in ashort & long acting version).

In another group of embodiments, are provided formulations (e.g. oral orparenteral formulations) comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, alone or in combination with other antibiotics in thequinolone, beta lactam, and macrolide classes, for use in treatingHelicobacter pylori infections and the diseases that they causeincluding peptic ulcers & gastroduadenal ulcers, chronic gastritis,gastric cancer and ulcerative colitis.

In yet another group of embodiments, is provided the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in a combinationproduct (e.g. a fixed dose combination product) with a beta lactamantibiotic for the prophylaxis and/or treatment of diseases related toH. Pylori Infection, (including metronidazole resistant H. Pyloriinfection).

(R)-ornidazole is highly active against strains of H. pylori (includingmetronidazole resistant strain of H. pylori) which cause clinicallyrelevant cases of chronic gastritis and ulcerative colitis and otherantibiotics are active against other causative species of bacteria inthese infections. Thus, a combination product of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole and such other antibiotic(s) isexpected to have superior efficacy in the treatment of these indicationscompared to known actives or the use of these agents alone. The productor combination product can be used as a therapeutic (e.g. fixed dosetherapeutic) fixed dose in oral sachet, oral solid, and parentalformulations.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment of H. pylori bacterial infections and theirrelated indications. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are rapidly absorbed after oral administration and hasa longer terminal elimination half-life (approximately 14-18 hours) thancommonly used drugs in the imidazole class. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole have an improved elimination halflife that enables more convenient dosing of oral formulations for theseH. pylori bacterial infections including sachet formulations of powderand or pelletized granules, capsules containing (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, oral solid tablet formulations,and liquid oral suspension formulations. These include sachetformulations with vehicles for varying absorbencies for delivery todifferent locations in the gastro-intestinal (GI) tract, capsulescontaining powders or pelletized granules with these properties, andoral solid tablet formulations with different types of slow releaseproperties. These formulations are particularly appropriate fortreatment of gram negative anaerobic bacteria like H. pylori that areresident in the GI tract, the typical site of infections in the abovementioned indications. In some case, parenteral formulations, such as(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in hydrochlorideform, are most appropriate for patients in certain clinical situationswhere oral formulation delivery is not feasible or advisable. Thedisposition of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole inthe human body is similar for both oral and intravenous dosage forms andthe present invention applies to the usage of both of these forms inthese settings.

Treatment of Diverticulitis

In one group of embodiments, the present invention provides the use of((R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in a combinationproduct (e.g. a fixed dose combination product) with a quinolone(including, but not limited to ciprofloxacin, levofloxacin, enoxacin,fleroxacin, & ofloxacin, for example selected from ciprofloxacin,levofloxacin, enoxacin, fleroxacin, & ofloxacin) antibiotic for theprophylaxis and treatment of simple and complicated diverticulitis.

In another group of embodiments, are provided formulations (e.g. oral orparenteral formulations) comprising (R)-ornidazole, alone or incombination with other antibiotics in the quinolone, beta lactam, andmacrolide classes, for use in treating simple and complicateddiverticulitis.

In yet another group of embodiments, is provided the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in a combinationproduct (e.g. a fixed dose combination product) with a beta lactamantibiotic for the prophylaxis and treatment of simple and complicateddiverticulitis.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst biofilms of Helicobacter pylori, Bacteroides species,Fusobacterium species, Clostridium species, Peptococcus species,Peptostreptococcus species, Eubacterium species, and Prevotella species,some of the bacteria which can contribute to causing clinically relevantcases of diverticulitis, and other antibiotics are active against othercausative species of bacteria in diverticulitis. Thus, combinationproduct of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole and suchother antibiotic(s) is expected to have superior efficacy in thetreatment of these indications compared to the use of these agentsalone. The combination product can be used as a fixed dose therapeuticin oral sachet, oral solid, and parental formulations.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment the above enumerated bacterial infections andtheir related indications. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are rapidly absorbed after oral administration and hasa longer terminal elimination half-life (approximately 14-18 hours) thancommonly used drugs in the imidazole class. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole have an elimination half life thatenables more convenient dosing of fixed dose oral formulations for thesebacterial infections including sachet formulations of powder and orpelletized granules, capsules containing (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole, oral solid tablet formulations, and liquid oralsuspension formulations. These include oral sachet, and oral solidtablet formulations with different types of slow release properties. Inmany of severe cases, parenteral formulations, such as (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole in hydrochloride form, are mostappropriate for patients in certain clinical situations where oralformulation delivery is not feasible or advisable. The disposition of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in the human bodyis similar for both oral and intravenous dosage forms and the presentinvention applies to the usage of both of these forms in these settings.

In the above embodiments relating to the treatment of diverticulitis,the diverticulitis may be uncomplicated diverticulitis or complicateddiverticulitis. In particular the diverticulitis is complicateddiverticulitis. As described hereinbefore, patients with complicateddiverticulitis generally require hospitalisation and infection isconfirmed in the diverticuli by for example obtaining a tissue samplefrom the patients. Generally the patient will require surgery inaddition to being treated with (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole. Patients with diverticulitis may be infected with forexample one or more pathogens selected from biofilms of PrevotellaSpecies, Bacteroides Species, Fusobacterium Species, Helicobacterpylori, Peprococcus Species and Peptostreptococcus Species. Accordinglyin a further embodiment of the invention there is provided(R)-ornidazole for use in the treatment of diverticulitis, particularlycomplicated diverticulitis, in a patient infected by one of morepathogens selected from biofilms of Prevotella Species, BacteroidesSpecies, Fusobacterium Species, Helicobacter pylori, Peprococcus Speciesand Peptostreptococcus Species.

Treatment of Diseases Related to H. Pylori Infection

In one group of embodiments, the present invention provides therapeuticuses of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in acombination product (e.g. a fixed dose combination product) with amacrolide (including, but not limited to erythromycin, clarithromycin, &azithromycin) antibiotic for the prophylaxis and treatment of diseasesrelated to H. Pylori Infection, (including metronidazole resistant H.Pylori infection), including, but not limited to peptic ulcers &gastroduadenal ulcers, chronic gastritis gastic cancer, and Crohn'sDisease. Additional embodiments of this fixed dose combination productwould also include a proton pump inhibitor (e.g. omeprazole) and or anantiinflammatory agent (e.g. Mesalamine, in a short & long actingversion).

In another group of embodiments, are provided formulations (e.g. oral orparenteral formulations) comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, alone or in combination with other antibiotics in thequinolone, beta lactam, and macrolide classes, for use in treatingHelicobacter pylori infections and the diseases that they causeincluding peptic ulcers & gastroduadenal ulcers, chronic Gastritis, andCrohn's Disease.

In yet another group of embodiments, is provided the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in a combinationproduct (e.g. a fixed dose combination product) with a beta lactamantibiotic for the prophylaxis and/or treatment of diseases related toH. Pylori biofilm infection, (including metronidazole resistant H.Pylori infection).

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst strains of H. pylori (including metronidazole resistant strainof H. pylori) which cause clinically relevant cases of peptic ulcers &gastroduadenal ulcers, chronic gastritis, and Crohn's Disease and otherantibiotics are active against other causative species of bacteria inthese infections. Thus, combination product of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole and such other antibiotic(s) isexpected to have superior efficacy in the treatment of these indicationscompared to known actives or the use of these agents alone. The productor combination product can be used as a therapeutic (e.g. fixed dosetherapeutic) fixed dose in oral sachet, oral solid, and parentalformulations.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment of H. pylori bacterial infections and theirrelated indications. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are rapidly absorbed after oral administration and hasa longer terminal elimination half-life (approximately 14-18 hours) thancommonly used drugs in the imidazole class. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole have an improved elimination halflife that enables more convenient dosing of oral formulations for theseH. pylori bacterial infections including sachet formulations of powderand or pelletized granules, capsules containing (R)-ornidazole, oralsolid tablet formulations, and liquid oral suspension formulations.These include sachet formulations with vehicles for varying absorbenciesfor delivery to different locations in the gastro-intestinal (GI) tract,capsules containing powders or pelletized granules with theseproperties, and oral solid tablet formulations with different types ofslow release properties. These formulations are particularly appropriatefor treatment of gram negative anaerobic bacteria like H. pylori thatare resident in the GI tract, the typical site of infections in theabove mentioned indications. In some case, parenteral formulations, suchas (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in hydrochlorideform, are most appropriate for patients in certain clinical situationswhere oral formulation delivery is not feasible or advisable. Thedisposition of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole inthe human body is similar for both oral and intravenous dosage forms andthe present invention applies to the usage of both of these forms inthese settings.

Treatment of Abdominal and Intra-Abdominal Infections

In one group of embodiments, the present invention provides the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in a combinationproduct (e.g. a fixed dose combination product) with a quinolone(including, but not limited to ciprofloxacin, levofloxacin, enoxacin,fleroxacin, & ofloxacin) antibiotic for the prophylaxis and treatment ofabdominal and intra-abdominal infections (including severe abdominal andintra-abdominal infections, e.g. peritonitis, intra-abdominal abscess,liver abscess).

In another group of embodiments, are provided formulations (e.g. oral orparenteral formulations) comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, alone or in combination with other antibiotics in thequinolone, beta lactam, and macrolide classes, for use in treatingabdominal and intra-abdominal infections (including severe abdominal andintra-abdominal infections, e.g. peritonitis, intra-abdominal abscess,liver abscess).

In yet another group of embodiments, is provided the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in a combinationproduct (e.g. a fixed dose combination product) with a beta lactamantibiotic for the prophylaxis and treatment of abdominal andintra-abdominal infections (including severe abdominal andintra-abdominal infections, e.g. peritonitis, intra-abdominal abscess,liver abscess).

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst biofilms of Bacteroides species including but not limited toBacteroides fragilis, Fusobacterium species, Clostridium species,Peptococcus species, Peptostreptococcus species, Eubacterium species,Prevotella species, the bacteria which cause clinically relevant casesof severe abdominal and intra-abdominal infections (including severeabdominal and intra-abdominal infections, e.g. peritonitis,intra-abdominal abscess, liver abscess) and other antibacterial agentsare active against other causative species of bacteria in theseinfections. Thus, combination product of (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole and such other antibiotic(s) is expected to havesuperior efficacy in the treatment of these indications compared to theuse of these agents alone. The combination product can be used as afixed dose therapeutic in oral sachet, oral solid, and parentalformulations.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment the above enumerated bacterial infections andtheir related indications. ((R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are rapidly absorbed after oral administration and hasa longer terminal elimination half-life (approximately 14-18 hours) thancommonly used drugs in the imidazole class. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole have an elimination half life thatenables more convenient dosing of fixed dose oral formulations for thesebacterial infections including sachet formulations of powder and orpelletized granules, capsules containing ((R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, oral solid tablet formulations,and liquid oral suspension formulations. These include oral sachet, andoral solid tablet formulations with different types of slow releaseproperties. These formulations, as well as fixed dose combinationparenteral formulations of these drugs, are particularly appropriate fortreatment of severe abdominal and intra-abdominal infections. Thedisposition of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole inthe human body is similar for both oral and intravenous dosage forms andthe present invention applies to the usage of both of these forms inthese settings.

Treatment of Skin Infections

In one group of embodiments, the present invention provides the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in a combinationproduct (e.g. a fixed dose combination product) with a quinolone(including, but not limited to ciprofloxacin, levofloxacin, enoxacin,fleroxacin, & ofloxacin) antibiotic for the prophylaxis and/or treatmentof complicated and uncomplicated skin infections including, but notlimited to, diabetic foot ulcers and surgical wound infections.

In another group of embodiments, are provided formulations (e.g. oral orparenteral formulations) comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, alone or in combination with other antibiotics in thequinolone, beta lactam, and macrolide classes, for use in treating skininfections (e.g. complicated and uncomplicated skin infections)including, but not limited to, diabetic foot ulcers and surgical woundinfections.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst anaerobic bacteria which cause many clinically relevant cases ofcomplicated and uncomplicated skin infections and quinolones are activeagainst other causative species of bacteria in these infections. Thus acombination product of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole and such other antibiotic(s) is expected to havesuperior efficacy in the treatment of these indications compared to theuse of these agents alone. The combination product can be used as afixed dose therapeutic in oral sachet, oral solid, and parentalformulations.

In addition, the pharmacologic parameters of ((R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of bacterial infections related to complicated and uncomplicatedskin infections. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare rapidly absorbed after oral administration and has a longer terminalelimination half-life (approximately 14-18 hours) than commonly useddrugs in the imidazole class. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole have an improved elimination half life that enablesmore convenient dosing of fixed dose oral formulations for thesebacterial infections including sachet formulations of powder and orpelletized granules, capsules containing (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole, oral solid tablet formulations, and liquid oralsuspension formulations. These include oral sachet, and oral solidtablet formulations with different types of slow release properties aswell as topical formulations. These formulations are particularlyappropriate for treatment of complicated and uncomplicated skininfections. In many of the most severe cases, parenteral formulations,such as (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole inhydrochloride form, are most appropriate for patients in these certainclinical situations where oral formulation delivery is not feasible oradvisable. The disposition of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole in the human body is similar for both oral andintravenous dosage forms and the present invention applies to the usageof both of these forms in these settings.

Treatment of Skin Infections in Combination Therapy

In one group of embodiments, the present invention provides the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in a combinationproduct (e.g. a fixed dose combination product) with a quinolone(including, but not limited to ciprofloxacin, levofloxacin, enoxacin,fleroxacin, & ofloxacin) antibiotic for the prophylaxis and/or treatmentof complicated and uncomplicated skin infections including, but notlimited to, diabetic foot ulcers and surgical wound infections.

In another group of embodiments, are provided formulations (e.g. oral orparenteral formulations) comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, alone or in combination with other antibiotics in thequinolone, beta lactam, and macrolide classes, for use in treating skininfections (e.g. complicated and uncomplicated skin infections)including, but not limited to, diabetic foot ulcers and surgical woundinfections

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst anaerobic bacteria which cause many clinically relevant cases ofcomplicated and uncomplicated skin infections and quinolones are activeagainst other causative species of bacteria in these infections. Thus acombination product of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole and such other antibiotic(s) is expected to havesuperior efficacy in the treatment of these indications compared to theuse of these agents alone. The combination product can be used as afixed dose therapeutic in oral sachet, oral solid, and parentalformulations.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of bacterial infections related to complicated and uncomplicatedskin infections. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazoleare rapidly absorbed after oral administration and has a longer terminalelimination half-life (approximately 14-18 hours) than commonly useddrugs in the imidazole class. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole have an improved elimination half life that enablesmore convenient dosing of fixed dose oral formulations for thesebacterial infections including sachet formulations of powder and orpelletized granules, capsules containing (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole, oral solid tablet formulations, and liquid oralsuspension formulations. These include oral sachet, and oral solidtablet formulations with different types of slow release properties aswell as topical formulations. These formulations are particularlyappropriate for treatment of complicated and uncomplicated skininfections. In many of the most severe cases, parenteral formulations,such as (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole inhydrochloride form, are most appropriate for patients in these certainclinical situations where oral formulation delivery is not feasible oradvisable. The disposition of ((R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole in the human body is similar for both oral andintravenous dosage forms and the present invention applies to the usageof both of these forms in these settings.

Treatment of Rosacea

In some embodiments of the present invention, there are providedformulations (e.g. topical formulations) comprising (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole for the treatment of rosacea. Inone embodiment (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole areadministered topically for the treatment of rosacea. This allows the useof higher dosages and concentrations than can be administeredsystemically. Appropriate topical formulations include gels, creams, andlotions for the treatment of either localised sites or larger surfaceareas.

Rosacea is a chronic condition characterized by facial erythema(redness). Pimples are sometimes included as part of the definition.Rosacea affects both sexes, but is almost three times more common inwomen. It has a peak age of onset between 30 and 60. Patients withrosacea have elevated levels of the peptide cathelicidin and elevatedlevels of stratum corneum tryptic enzymes (SCTEs). (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole in rosacea works, in part, becauseit inhibits some SCTEs as well as intestinal bacteria (small intestinalbacterial overgrowth [SIBO]) which play a role in causing the disease.Bacillus oleronius may also be implicated in rosacea and accordingly theinhibition or eradication of this organism by administering, suitablytopically, a therapeutically effective dose of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole may be beneficial in the treatmentof rosacea. Accordingly in a further embodiment there is provided(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole for use in thetreatment of rosacea associated with Bacillus oleronius.

While the exact mechanism of action and pharmacodynamics of both topicaland systemic oral treatment with (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole in rosacea is unknown, the result of treatment isefficacious.

Treatment of Fungating Tumors

In some embodiments of the invention, there are provided formulations(e.g. topical and systemic, including both oral and intravenousformulations) comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole for the treatment of fungating tumors or lesions.

A fungating tumor or lesion is a type of skin lesion that is marked byulcerations (breaks on the skin or surface of an organ) and necrosis(death of living tissue) and that usually has a bad smell, oftenassociated with the presence of gram negative anaerobic bacteria. Thiskind of lesion may occur in many types of cancer, including breastcancer, melanoma, and squamous cell carcinoma, and especially inadvanced disease.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole treats thecondition through a variety of mechanisms, including, but not limitedto, eradicating the gram negative anaerobic bacteria in the tissue.

Treatment of Decubitus Ulcers

In some embodiments of the invention, there are provided formulations(e.g. topical and systemic, including both oral and intravenousformulations) comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, either alone or in combination with other antibiotics,for the treatment of decubitus ulcers (bed sores).

Bedsores, more properly known as pressure ulcers or decubitus ulcers,are lesions caused by many factors such as: unrelieved pressure;friction; humidity; shearing forces; temperature; age; continence andmedication; to any part of the body, especially portions over bony orcartilaginous areas such as sacrum, elbows, knees, and ankles. Althoughoften prevented and treatable if found early, they can be very difficultto prevent in frail elderly patients, wheelchair users (especially wherespinal injury is involved) and terminally ill patients. Bedsores areoften fatal—even under the auspices of medical care—and are one of theleading iatrogenic causes of death reported in developed countries,second only to adverse drug reactions. The primary cure and treatment isto remove the pressure by turning the patient regularly. Frequently,tissue damaged through decubitus ulcers becomes infected with a varietyof gram negative bacteria which both complicates the treatment of theulcers and can pose life threatening consequences if the patient becomesseptic.

Treatment with (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, intopical, oral systemic and intravenous formulations, either alone or incombination with other antibiotics, can eradicate the causativepathogens in these infections.

Treatment of Borrelia (e.g. Borrelia burgdorferi) Infections e.g. LymeDisease

In one group of embodiments, the present invention provides therapeuticuses of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in acombination product (e.g. a fixed dose combination product) with amacrolide (including, but not limited to erythromycin, clarithromycin, &azithromycin) or tetracycline antibiotic for the treatment of LymeDisease (including bacterial infections caused by biofilms of Borreliaburgdorferi and other instances of Lyme disease caused by otherBorrelia).

In another group of embodiments, the present invention providestherapeutic uses of (R)-ornidazole in different oral, topical andparenteral formulations for the treatment of bacterial infectionsincluding Lyme Disease (e.g. that caused by Borrelia burgdorferi).(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole is effective incombination with one or more antibiotics in the beta lactam (penicillin& cephalosporin), tetracycline, and macrolide classes of antibioticswhere there is a likelihood of the presence of the biofilm and cysticform of the bacteria as well as other forms highly sensitive to theseother classes of drugs.

Lyme Disease incidence has increased dramatically in the United Statesto the point that the disease has become an important public healthproblem. Today, Lyme Disease is the most prevalent tick-borne illness inthe United States. Borrelia burgdorferi consists of three strainssensitive to (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole,collectively known as Borrelia burgdorferi sensu lato. These genospeciesare Borrelia burgdorferi sensu strict, Borrelia garinii, and Borreliaafzelii. In addition the genospecies Borrelia valaisiana is also asuspected pathogenic strain implicated in Lyme Disease (Lyme borreliosisin Europe influences of climate and climate change, epidemiology,ecology and adaptation measures; Elisabet Lindgren and Thomas G. T.Jaenson; WHO Report on project number (EVK2-2000-00070)). The Borreliavalaisiana strain may also be susceptible to treatment with(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole).

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst the biofilm and cystic form of Borrelia burgdorferi, unlike manyother antibiotics, and macrolides and β-lactam antibiotics are highlyactive against the other forms of Borrelia burgdorferi, (e.g. thecorkscrew form) Thus, the combination products of the invention will behave superior efficacy in these mixed form infection settings of LymeDisease. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole cantherefore be used as an antibiotic to treat these infections either in afixed dose tetracycline or macrolide combination that is active againstBorrelia burgdorferi sensu lato spirochete bacteria or a single agent insensitive strains.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment of Borrelia burgdorferi bacterial infectionsand their related indication. (R)-omidazole, (S)-ornidazole, and(rac)-ornidazole are rapidly absorbed after oral administration and hasa longer terminal elimination half-life (approximately 14-18 hours) thancommonly used drugs in the imidazole class. (R)-ornidazole has anelimination half life that enables more convenient dosing of oralformulations for these Borrelia burgdorferi bacterial infectionsincluding sachet formulations of powder and or pelletized granules,capsules containing (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, oral solid tablet formulations, and liquid oralsuspension formulations. These include sachet formulations with vehiclesfor varying absorbencies for delivery to different locations in thegastro-intestinal (GI) tract, capsules containing powders or pelletizedgranules with these properties, and oral solid tablet formulations withdifferent types of slow release properties. These formulations areparticularly appropriate for treatment of gram negative bacteria likeBorrelia burgdorferi. In some case, parenteral formulations, such as(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in hydrochlorideform, are most appropriate for patients in certain clinical situationswhere oral formulation delivery is not feasible or advisable. Thedisposition of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole inthe human body is similar for both oral and intravenous dosage forms andthe present invention applies to the usage of both of these forms inthese settings.

Treatment of Burkholderia Infections

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, for use in thetreatment of Glanders and Melioidosis infections wherein the Glandersand Melioidosis infections are caused by biofilms of Burkholderia malleior Burholderia pseudomallei and at least some of the bacteria arepresent in an aneroebic configuration.

In another embodiment, the (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are for use in combination to treat Burkholderiainfections with one or more antibiotics, the antibiotics being selectedfrom β-lactam antibiotics (including amoxiclav), tetracyclineantibiotics, penem antibiotics, quinolone antibiotics and macrolideantibiotics.

Treatment of Coxiella Infections

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, orpharmaceutically acceptable salts or esters thereof, for use in thetreatment of Q-fever infections wherein the Q-fever infections arecaused by Coxiella burnetii and at least some of the bacteria arepresent in an aneroebic configuration.

In another embodiment, (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole in Coxiella and Q-fever infections is for use incombination with one or more antibiotics, the antibiotics being selectedfrom β-lactam antibiotics, tetracycline antibiotics, penem antibiotics,quinolone antibiotics and macrolide antibiotics.

Coxiella burnetii is an obligate intracellular bacterial pathogen, andis the causative agent of Q fever. The genus Coxiella is morphologicallysimilar to Rickettsia, but with a variety of genetic and physiologicaldifferences. C. burnetii is a small Gram-negative bacterium that ishighly resistant to environmental stresses such as high temperature,osmotic pressure, and ultraviolet light. These characteristics areattributed to a small cell variant form of the organism that is part ofa biphasic developmental cycle, including a more metabolically andreplicatively active large cell variant form.

Treatment of Lung Infections

In one group of embodiments, they are provided formulations (e.g. oralor parenteral formulations) comprising (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole, alone or in combination with other antibioticsincluding, but not limited to, those in the quinolone, beta lactam, andmacrolide classes, for use in treating lung infections including, butnot limited to, emphysema, pneumonia & aspiration pneumonia, Lemmiere'sSyndrome and lung abscess.

Because (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highlyactive against anaerobic bacteria which cause clinically relevant casesof pulmonary related infections, it will be used as therapeutic in oralsachet, oral solid, and parental formulations in these settings.(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole can therefore beused as an antibiotic to treat these infections either alone or incombination with other antibiotics that are active against these gramnegative anaerobe bacteria including, but not limited to quinolone, betalactam, and macrolide classes of antibiotics.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment of the above enumerated gram negative bacterialinfections related to pulmonary associated infections. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole are rapidly absorbed after oraladministration and has a longer terminal elimination half-life(approximately 14-18 hours) than commonly used drugs in the imidazoleclass. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole have animproved elimination half life that enables more convenient dosing oforal formulations for these gram negative bacterial infections includingsachet formulations of powder and or pelletized granules, capsulescontaining ((R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, oralsolid tablet formulations, and liquid oral suspension formulations.These include oral sachet and oral solid tablet formulations withdifferent types of slow release properties. These formulations areparticularly appropriate for treatment of the above enumerated gramnegative anaerobic bacteria. In many of these severe cases, parenteralformulations, such as (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole in hydrochloride form, are most appropriate forpatients in these certain clinical situations where oral formulationdelivery is not feasible or advisable. The disposition of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in the human bodyis similar for both oral and intravenous dosage forms and the presentinvention applies to the usage of both of these forms in these settings.

Treatment of Central Nervous System Infections

In one group of embodiments, are provided formulations (e.g. oral orparenteral formulations) comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, alone or in combination with other antibioticsincluding, but not limited to, those in the quinolone, beta lactam, andmacrolide classes, for use in treating central nervous system relatedinfections including, but not limited to, meningitis and brain abscessesand infection related conditions including autism and Parkinson'sDisease.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst anaerobic bacteria which cause clinically relevant cases ofcentral nervous system related infections, it will be used astherapeutic in oral sachet, oral solid, and parental formulations inthese settings. ((R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolecan therefore be used as an antibiotic to treat these infections eitheralone or in combination with other antibiotics that are active againstthese gram negative anaerobe bacteria including, but not limited toquinolone, beta lactam, and macrolide classes of antibiotics.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment of the above enumerated gram negative bacterialinfections related to central nervous system infections. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole are rapidly absorbed after oraladministration and has a longer terminal elimination half-life(approximately 14-18 hours) than commonly used drugs in the imidazoleclass. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole have anelimination half life that enables more convenient dosing of oralformulations for these gram negative bacterial infections includingsachet formulations of powder and or pelletized granules, capsulescontaining (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, oralsolid tablet formulations, and liquid oral suspension formulations.These include sachet, oral solid tablet formulations with differenttypes of slow release properties, and vaginal suppository/topicalformulations. These formulations are particularly appropriate fortreatment of the above enumerated gram negative anaerobic bacteria. Inmany of these severe cases, parenteral formulations, such as(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in hydrochlorideform, are most appropriate for patients in these certain clinicalsituations where oral formulation delivery is not feasible or advisable.The disposition of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolein the human body is similar for both oral and intravenous dosage formsand the present invention applies to the usage of both of these forms inthese settings.

Autism is a highly variable neurodevelopmental disorder that firstappears during infancy or childhood, and generally follows a steadycourse without remission. Overt symptoms gradually begin after the ageof six months, become established by age two or three years, and tend tocontinue through adulthood, although often in more muted form. It isdistinguished not by a single symptom, but by a characteristic triad ofsymptoms: impairments in social interaction; impairments incommunication; and restricted interests and repetitive behavior.Atypical eating is common and is related to dysbiosis of GI microbiota.This unusual eating behavior occurs in about three-quarters of childrenwith ASD. Autism symptoms in patients have been mitigated throughantibiotic manipulation of microbiota in the GI system with vancomycinand will respond better to (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole given the range of bacteria affected and shifted in thebeta dimension of compositional diversity.

Parkinson's disease is a degenerative disorder of the central nervoussystem. The motor symptoms of Parkinson's disease result from the deathof dopamine-generating cells in the substantia nigra, a region of themidbrain; the cause of this cell death is unknown. Early in the courseof the disease, the most obvious symptoms are movement-related; theseinclude shaking, rigidity, slowness of movement and difficulty withwalking and gait. Atypical microbiota enterotypes in Parkinson's diseaseis related to dysbiosis of GI microbiota. Parkinson's disease symptomsin patients can be mitigated through antibiotic manipulation ofmicrobiota in the GI system with ((R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole given the range of bacteria affected and shifted in thebeta dimension of compositional diversity.

Treatment Blood Infections

In one group of embodiments, are provided formulations (e.g. oral orparenteral formulations) comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, alone or in combination with other antibioticsincluding, but not limited to, those in the quinolone, beta lactam,penem and macrolide classes, for use in treating blood infectionsincluding, but not limited to, bacteremia and septicemia.

Because (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highlyactive against anaerobic bacteria which cause clinically relevant casesof blood stream related infections, it can be used as therapeutic inoral sachet, oral solid, and parental formulations in these settings.(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole can therefore beused as an antibiotic to treat these infections either alone or incombination with other antibiotics that are active against these gramnegative anaerobe bacteria including, but not limited to quinolone, betalactam, penem, and macrolide classes of antibiotics.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment of the above enumerated gram negative bacterialinfections related to central nervous system infections. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole are rapidly absorbed after oraladministration and has a longer terminal elimination half-life(approximately 14-18 hours) than commonly used drugs in the imidazoleclass. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole have anelimination half life that enables more convenient dosing of oralformulations for these gram negative bacterial infections includingsachet formulations of powder and or pelletized granules, capsulescontaining (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, oralsolid tablet formulations, and liquid oral suspension formulations.These include oral sachet and oral solid tablet formulations withdifferent types of slow release properties. These formulations areparticularly appropriate for treatment of the above enumerated gramnegative anaerobic bacteria. In many of these severe cases, parenteralformulations, such as (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole in hydrochloride form, are most appropriate forpatients in these certain clinical situations where oral formulationdelivery is not feasible or advisable. The disposition of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in the human bodyis similar for both oral and intravenous dosage forms and the presentinvention applies to the usage of both of these forms in these settings.

Treatment of Bone and Joint Infections

In one group of embodiments, there are provided formulations (e.g. oralor parenteral formulations) comprising (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole, alone or in combination with other antibioticsincluding, but not limited to, those in the tetracycline, quinolone,beta lactam, penem and macrolide classes, for use in treating bone andjoint related infections.

Because (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highlyactive against anaerobic bacteria which cause clinically relevant casesof bone and joint related infections, it can be used as therapeutic inoral sachet, oral solid, and parental formulations in these settings.(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole can therefore beused as an antibiotic to treat these infections either alone or incombination with other antibiotics that are active against these gramnegative anaerobe bacteria including, but not limited to quinolone, betalactam, penem, and macrolide classes of antibiotics.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make it appropriate to use in thesetting of the treatment of the above enumerated gram negative bacterialinfections related to central nervous system infections. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole are rapidly absorbed after oraladministration and has a longer terminal elimination half-life(approximately 14-18 hours) than commonly used drugs in the imidazoleclass. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole have anelimination half life that enables more convenient dosing of oralformulations for these gram negative bacterial infections includingsachet formulations of powder and or pelletized granules, capsulescontaining (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, oralsolid tablet formulations, and liquid oral suspension formulations.These include oral sachet and oral solid tablet formulations withdifferent types of slow release properties. These formulations areparticularly appropriate for treatment of the above enumerated gramnegative anaerobic bacteria. In many of these severe cases, parenteralformulations, such as (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole in hydrochloride form, are most appropriate forpatients in these certain clinical situations where oral formulationdelivery is not feasible or advisable. The disposition of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in the human bodyis similar for both oral and intravenous dosage forms and the presentinvention applies to the usage of both of these forms in these settings.

Treatment of Heart Infections

In one group of embodiments, are provided formulations (e.g. oral orparenteral formulations) comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, alone or in combination with other antibioticsincluding, but not limited to, those in the quinolone, beta lactam,penem, and macrolide classes, for use in treating heart infectionsincluding but not limited to endocarditis.

Because (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highlyactive against anaerobic bacteria which cause clinically relevant casesof cause cardiac related infections, it can be used as therapeutic inoral sachet, oral solid, and parental formulations in these settings.(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole can therefore beused as an antibiotic to treat these infections either alone or incombination with other antibiotics that are active against these gramnegative anaerobe bacteria including, but not limited to quinolone, betalactam, penem, and macrolide classes of antibiotics.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment of the above enumerated gram negative bacterialinfections related to central nervous system infections. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole are rapidly absorbed after oraladministration and has a longer terminal elimination half-life(approximately 14-18 hours) than commonly used drugs in the imidazoleclass. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole have anelimination half life that enables more convenient dosing of oralformulations for these gram negative bacterial infections includingsachet formulations of powder and or pelletized granules, capsulescontaining (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, oralsolid tablet formulations, and liquid oral suspension formulations.These include oral sachet and oral solid tablet formulations withdifferent types of slow release properties. These formulations areparticularly appropriate for treatment of the above enumerated gramnegative anaerobic bacteria. In many of these severe cases, parenteralformulations, such as (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole in hydrochloride form, are most appropriate forpatients in these certain clinical situations where oral formulationdelivery is not feasible or advisable. The disposition of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in the human bodyis similar for both oral and intravenous dosage forms and the presentinvention applies to the usage of both of these forms in these settings.

Treatment of Venereal Disease or Sexually Transmitted Disease (STD)

Syphilis is a sexually transmitted infection caused by the spirochetebacterium Treponema pallidum subspecies pallidum. The primary route oftransmission is through sexual contact; it may also be transmitted frommother to fetus during pregnancy or at birth, resulting in congenitalsyphilis. Other human diseases caused by related Treponemapalliduminclude yaws (subspecies pertenue), pinta (subspecies carateum), andbejel (subspecies endemicum).

Because (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highlyactive against biofilms of anaerobic bacteria which cause clinicallyrelevant cases of syphilis and yaws, it can be used as therapeutic inoral sachet, oral solid, and parental formulations in these settings.(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole can therefore beused as an antibiotic to treat these infections either alone or incombination with other antibiotics that are active against these gramnegative anaerobe bacteria including, but not limited to quinolone, betalactam, penem, and macrolide classes of antibiotics.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment of the above enumerated gram negative bacterialinfections related to syphilis and yaws infections. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole are rapidly absorbed after oraladministration and has a longer terminal elimination half-life(approximately 14-18 hours) than commonly used drugs in the imidazoleclass. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole have anelimination half life that enables more convenient dosing of oralformulations for these gram negative bacterial infections includingsachet formulations of powder and or pelletized granules, capsulescontaining (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, oralsolid tablet formulations, and liquid oral suspension formulations.These include oral sachet and oral solid tablet formulations withdifferent types of slow release properties. These formulations areparticularly appropriate for treatment of the above enumerated gramnegative anaerobic bacteria. In many of these severe cases, parenteralformulations, such as (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole in hydrochloride form, are most appropriate forpatients in these certain clinical situations where oral formulationdelivery is not feasible or advisable. The disposition of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in the human bodyis similar for both oral and intravenous dosage forms and the presentinvention applies to the usage of both of these forms in these settings.

Bacterial urethritis is inflammation of the urethra caused by bacteria.The urethra is the tube that carries urine from the bladder to outsidethe body. Pain with urination is the main symptom of bacterialurethritis. Bacterial urethritis is due to infection by bacteria throughsexual contact. It can be cured with (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole.

Prevention of Sexually Transmitted Disease (STD) Transmission

A key favorable condition for transmission of sexually transmitteddiseases (STDs), including, but not limited to, human immunodeficiencyvirus (HIV), herpes simplex virus (HSV), hepatitis C virus (HCV),hepatitis B virus (HBV), human papilloma virus (HPV), gonorrhea, andsyphilis, is changes that occur in the normal balance between organismsin the vagina when the number of protective bacteria like Lactobacillidecrease. This often occurs in a situation of bacterial vaginosis.Hence, bacterial vaginosis, by reducing the presence of lactic acidproducing Lactobacilli and the breakdown of the vaginal mucosal barrierby other overgrowing bacterial species such as Bacteroides species andGardnerella species, predisposes these women to getting the abovedelineated STDs. Because the underlying cause of the breakdown of thephysical vaginal mucosal barrier and its pH chemical barrier from lacticacid is a bacterial infection that creates a suitable environment forpathogenic bacteria overgrowth, the treatment of bacterial vaginitiswith an effective antibacterial agent will diminish the transmission ofthe these STD infections. In cases with multiple types of bacteria beingovergrown, ie, bacterial vaginosis or in an overgrowth of vaginalprotozoal pathogens (trichomoniasis), it has been shown that infectionsare a major risk factors in HIV transmission as well as the transmissionof the other STDs listed above. Treatment with a combination of anantibiotic and anti-protozoal agent will prevent the sexual transmissionof these STDs by infected males or females to susceptible females witheither symptomatic or asymptomatic bacterial vaginitis or vaginosis byeliminating the overgrowth of pathogen bacteria or protozoa and there-establishment of the natural predominant commensal Lactobacilliflora.

In one group of embodiments, the present invention provides the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, (e.g. in either anoral or vaginal formulation), in combination with antifungal drugsactive against Candida albicans (including, but not limited tofluconazole, miconazole nitrate, clotrimazole, econazole, saperconazole,terconazole, fenticonazole, sertaconazole, posaconazole, itraconazole,ketoconazole, butaconazole, tioconazole, cyclopirox, caspofungin,micafungin, and anidulafungin) for the prevention of STD transmissionrelated to bacterial vaginosis and/or trichmoniasis and/or vaginalcandidiasis. The antifungal drug may be in the form of a vaginal topicalor systemic (e.g. oral) formulation. A single dose treatment with anoral sachet formulation of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole may be the only administration of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole during the entire treatment.

In the above section, and throughout this specification, the term‘prevention of STD transmission’ means eliminating or reducing the riskof said transmission.

If present, the single dose treatment oral sachet formulation and thevaginal topical or systemic (e.g. oral) formulation of the antifungaldrug may be provided in the form of a kit.

Treatment of Urinary Tract Infections

In one group of embodiments, the present invention provides the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in a combinationproduct (e.g. a fixed dose combination product) with a quinolone(including, but not limited to ciprofloxacin, levofloxacin, enoxacin,fleroxacin, & ofloxacin) antibiotic for the prophylaxis and treatment ofurinary tract infections (e.g. complicated and uncomplicated urinarytract infections).

In another group of embodiments, are provided formulations (e.g. oral orparenteral formulations) comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, alone or in combination with other antibiotics in thequinolone, beta lactam, and macrolide classes, for use in treatingurinary tract infections (e.g. complicated and uncomplicated urinarytract infections).

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst anaerobic bacteria which cause many clinically relevant cases ofcomplicated and uncomplicated urinary tract infections and otherantibiotics are active against other causative species of bacteria inthese infections. Thus combination product of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole and such other antibiotic(s) isexpected to have superior efficacy in the treatment of these indicationscompared to the use of these agents alone. The combination product canbe used as a fixed dose therapeutic in oral sachet, oral solid, andparental formulations.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of bacterial infections related to complicated and uncomplicatedurinary tract infections. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are rapidly absorbed after oral administration and hasa longer terminal elimination half-life (approximately 14-18 hours) thancommonly used drugs in the imidazole class. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole have an elimination half life thatenables more convenient dosing of fixed dose oral formulations for thesebacterial infections including sachet formulations of powder and orpelletized granules, capsules containing (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole, oral solid tablet formulations, and liquid oralsuspension formulations. These include sachet, and oral solid tabletformulations with different types of slow release properties. Theseformulations are particularly appropriate for treatment of infectionscaused by bacteria resident in the urinary tract. In many of the mostsevere cases, parenteral formulations, such as (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole in hydrochloride form, are mostappropriate for patients in these certain clinical situations where oralformulation delivery is not feasible or advisable. The disposition of(R)-ornidazole in the human body is similar for both oral andintravenous dosage forms and the present invention applies to the usageof both of these forms in these settings.

Treatment of Pelvic Inflammatory Disease and Endometritis

In one group of embodiments, the present invention provides the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in a combinationproduct (e.g. a fixed dose combination product) with a quinolone(including, but not limited to ciprofloxacin, levofloxacin, enoxacin,fleroxacin, & ofloxacin) antibiotic for the prophylaxis and treatment ofpelvic inflammatory disease and endometritis.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst gram negative anaerobic bacteria which can contribute to causingclinically relevant cases of pelvic inflammatory disease andendometritis, and quinolones are active against other causative speciesof bacteria in pelvic inflammatory disease and endometritis. Thus,combination product of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole and such other antibiotic(s) is expected to havesuperior efficacy in the treatment of these indications compared to theuse of these agents alone. The combination product can be used as afixed dose therapeutic in oral sachet, oral solid, and parentalformulations.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make it appropriate to use in thesetting of the treatment the above enumerated bacterial infections andtheir related indications. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are rapidly absorbed after oral administration and hasa longer terminal elimination half-life (approximately 14-18 hours) thancommonly used drugs in the imidazole class. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole have an elimination half life thatenables more convenient dosing of fixed dose oral formulations for thesebacterial infections including sachet formulations of powder and orpelletized granules, capsules containing (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole, oral solid tablet formulations, and liquid oralsuspension formulations. These include oral sachet, and oral solidtablet formulations with different types of slow release properties.

Treatment of Endometritis and Endomyometritis

In one group of embodiments, is provided the use of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole (e.g. as an oral, vaginal topicalor parenteral formulation) for the treatment of endometritis.

Endometritis refers to inflammation of the endometrium, the inner liningof the uterus. Pathologists have traditionally classified endometritisas either acute or chronic: acute endometritis is characterized by thepresence of microabscesses or neutrophils within the endometrial glands,while chronic endometritis is distinguished by variable numbers ofplasma cells within the endometrial stroma. The most common cause ofendometritis is infection. Symptoms include lower abdominal pain, feverand abnormal vaginal bleeding or discharge. The present invention is forthe treatment of endometritis with (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole in different parenteral, oral and vaginal formulations(including topical vaginal and dissolvable vaginal ampoules), alsoincluding a single dose treatment of an oral sachet formulation for theentire treatment for a course of therapy. This treatment eradicatesstrains of the causative bacterial pathogens that are both sensitive andresistant to other antibacterial agents and in women who are bothsymptomatic and asymptomatic with endometritis.

In one group of embodiments, the present invention provides the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in a combinationproduct (e.g. a fixed dose combination product) with a quinolone(including, but not limited to ciprofloxacin, levofloxacin, enoxacin,fleroxacin, & ofloxacin) antibiotic for the prophylaxis and treatment ofendometritis.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst gram negative anaerobic bacteria which can contribute to causingclinically relevant cases of endometritis, and quinolones are activeagainst other causative species of bacteria in pelvic inflammatorydisease and endometritis. Thus, combination product of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole and such other antibiotic(s) isexpected to have superior efficacy in the treatment of these indicationscompared to the use of these agents alone. The combination product canbe used as a fixed dose therapeutic in oral sachet, oral solid, andparental formulations.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment the above enumerated bacterial infections andtheir related indications. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are rapidly absorbed after oral administration and hasa longer terminal elimination half-life (approximately 14-18 hours) thancommonly used drugs in the imidazole class. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole have an elimination half life thatenables more convenient dosing of fixed dose oral formulations for thesebacterial infections including sachet formulations of powder and orpelletized granules, capsules containing (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole, oral solid tablet formulations, and liquid oralsuspension formulations. These include oral sachet, and oral solidtablet formulations with different types of slow release properties.

In one group of embodiments, is provided the use of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole (e.g. as an oral, vaginal topicalor parenteral formulation) for the treatment of endomyometritis.

The term “endomyometritis” is sometimes used to specify inflammation ofthe endometrium and the myometrium. The most common cause ofendomyometritis is infection. Symptoms include lower abdominal pain,fever and abnormal vaginal bleeding or discharge. The present inventionis for the treatment of endomyometritis with rac-ornidazole in differentparenteral, oral and vaginal formulations (including topical vaginal anddissolvable vaginal ampoules), also including a single dose treatment ofan oral sachet formulation for the entire treatment for a course oftherapy. This treatment eradicates strains of the causative bacterialpathogens that are both sensitive and resistant to other antibacterialagents and in women who are both symptomatic and asymptomatic withendomyometritis.

Endometritis

In one group of embodiments, is provided the use of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole (e.g. as a oral, vaginal topical orparenteral formulation) for the treatment of endometritis.

Endometritis refers to inflammation of the endometrium, the inner liningof the uterus. Pathologists have traditionally classified endometritisas either acute or chronic: acute endometritis is characterized by thepresence of microabscesses or neutrophils within the endometrial glands,while chronic endometritis is distinguished by variable numbers ofplasma cells within the endometrial stroma. The most common cause ofendometritis is infection Symptoms include lower abdominal pain, feverand abnormal vaginal bleeding or discharge. The present invention is forthe treatment of endometritis with the (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole in different parenteral, oral and vaginalformulations (including topical vaginal and dissolvable vaginalampoules), also including a single dose treatment of an oral sachetformulation for the entire treatment for a course of therapy. Thistreatment eradicates strains of the causative bacterial pathogens thatare both sensitive and resistant to other antibacterial agents and inwomen who are both symptomatic and asymptomatic with endometritis.

Endomyometritis

In one group of embodiments, is provided the use of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole (e.g. as an oral, vaginal topicalor parenteral formulation) for the treatment of endometritis.

The term “endomyometritis” is sometimes used to specify inflammation ofthe endometrium and the myometrium. The most common cause ofendomyometritis is infection. Symptoms include lower abdominal pain,fever and abnormal vaginal bleeding or discharge. The present inventionis for the treatment of endomyometritis with (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole in different parenteral, oral andvaginal formulations (including topical vaginal and dissolvable vaginalampoules), also including a single dose treatment of an oral sachetformulation for the entire treatment for a course of therapy. Thistreatment eradicates strains of the causative bacterial pathogens thatare both sensitive and resistant to other antibacterial agents and inwomen who are both symptomatic and asymptomatic with endomyometritis.

Tubo-Ovarian Abscess

In one group of embodiments, is provided the use of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole (e.g. as an oral, vaginal topicalor parenteral formulation) for the treatment of a tubo-ovarian abscess.

A tubo-ovarian abscess (TOA) is an inflammatory mass involving thefallopian tube, ovary, and, occasionally, other adjacent pelvic organs(e.g., bowel, bladder). These abscesses are found most commonly inreproductive age women and typically result from upper genital tractinfection.

Tubo-ovarian abscess is a serious and potentially life-threateningcondition. Aggressive medical and/or surgical therapy is required andrupture of an abscess may result in sepsis. Prior to the advent ofbroad-spectrum antibiotics and modern surgical practice, the mortalityrate associated with tubo-ovarian abscess was approximately 50 percentor higher.

The present invention is for the treatment of TOA with the(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in differentparenteral, oral and vaginal formulations (including topical vaginal anddissolvable vaginal ampoules), also including a single dose treatment ofan oral sachet formulation for the entire treatment for a course oftherapy. This treatment eradicates strains of the causative bacterialpathogens that are both sensitive and resistant to other antibacterialagents and in women who have TOA.

Postsurgical Vaginal Cuff Infection

In one group of embodiments, is provided the use of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole (e.g. as an oral, vaginal topicalor parenteral formulation) for the treatment of vaginal cuff infection(e.g. post-surgical vaginal cuff infection).

Total abdominal hysterectomy is the most common procedure for removingthe uterus. Infection of the vaginal cuff is commonly reported as acomplication of this surgical procedure. The causative pathogens forvaginal cuff infections are the same pathogens found in bacterialvaginosis.

The present invention is for the treatment of postsurgical vaginal cuffinfection with (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole indifferent parenteral, oral and vaginal formulations (including topicalvaginal and dissolvable vaginal ampoules), also including a single dosetreatment of an oral sachet formulation for the entire treatment for acourse of therapy. This treatment eradicates strains of the causativebacterial pathogens that are both sensitive and resistant to otherantibacterial agents and in women who have postsurgical vaginal cuffinfections.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment the above enumerated bacterial infections andtheir related indications. (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole are rapidly absorbed after oral administration and havea longer terminal elimination half-life (approximately 14-18 hours) thancommonly used drugs in the imidazole class. (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole have an improved elimination halflife that enables more convenient dosing of fixed dose oral formulationsfor these bacterial infections including sachet formulations of powderand or pelletized granules, capsules containing (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole, oral solid tablet formulations,and liquid oral suspension formulations. These include oral sachet, andoral solid tablet formulations with different types of slow releaseproperties.

Treatment of Vulvovaginitis

Vulvovaginitis is an inflammation of the vagina and or vulva. It canresult in discharge, itching and pain. The three main causes ofvulvovaginitis are bacterial vaginosis (BV), vaginal candidiasis, andtrichomoniasis. A woman may have any combination of vaginal infectionsat one time. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole areeffective alone in treating bacterial vaginosis and trichmoniasis andcan be used in combination (e.g. a fixed dose combination) with anantifungal drug to prevent bacterial or protozoal super-infection withmixed infections of fungal pathogens, bacterial pathogens, and protozoalpathogens. The symptoms that arise vary with the infection, althoughthere are general symptoms that all vaginitis infections have and itmust be noted that infected women may also be asymptomatic. The presentinvention treats both symptomatic and asymptomatic infections arisingfrom strains of bacteria that cause bacterial vaginosis as well asprotozoa causing trichomoniasis, and the fungi that cause vaginalcandidiasis.

In one group of embodiments, the present invention provides the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, (e.g. in either anoral or vaginal formulation), in combination with antifungal drugsactive against Candida albicans (including, but not limited tofluconazole, miconazole nitrate, clotrimazole, econazole, saperconazole,terconazole, fenticonazole, sertaconazole, posaconazole, itraconazole,ketoconazole, butaconazole, tioconazole, cyclopirox, caspofungin,micafungin, and anidulafungin) for the treatment of vulvovaginitis. Theantifungal drug may be in the form of a vaginal topical or systemic(e.g. oral) formulation. A single dose treatment with an oral sachetformulation of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole maybe the only administration of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole for the entire treatment.

If present, the single dose treatment oral sachet formulation and thevaginal topical or systemic (e.g. oral) formulation of the antifungaldrug may be provided in the form of a kit.

This treatment is effective for strains of the causative bacterial,fungal, and protozoal pathogens that are both sensitive and resistant toother antibacterial, anti-protozoal and anti-fungal agents. In manycases the bacterial, protozoal, and fungal infections are either mixedor induce each other by altering the normal flora of the vagina. Thepresent invention can allow more convenient empiric treatment as well astreatment when the presence of both fungal and bacterial or protozoalpathogens has been demonstrated. This can prevent secondarysuper-infections, reduce morbidity and medical expense, and speedrecovery. The fixed doses combination drugs have the necessary spectrumof activity to eradicate common causative bacterial, protozoal andfungal pathogens together for concurrent treatment and also will haveformulations appropriate to treatment at either the vaginal site ofinfection, systemic infection, or both.

Treatment of Bacterial Vaginosis

Bacterial vaginosis (BV) is a disease of the vagina caused by bacterialovergrowth of normally predominant lactic acid and hydrogen peroxideproducing Lactobacilli bacteria (Lactobacilli species) by biofilms ofother species of bacteria including, but not limited to, Gardnerellavaginalis, Bacteroides species, Prevotella species, and Mobiluncusspecies. In clinical practice BV is diagnosed using the Amsel criteria:

1. Thin, white, yellow, homogeneous discharge

2. Clue cells on microscopy

3. pH of vaginal fluid >4.5

4. Release of a fishy odor on adding alkali—10% potassium hydroxide(KOH) solution.

At least three of the four criteria should be present for a confirmeddiagnosis. An alternative is to use a Gram-stained vaginal smear, withthe Nugent criteria. The standards for research are the Nugent Criteria.In this scale, a score of 0-10 is generated from combining three otherscores. The scores are as follows:

-   -   0-3 is considered negative for BV    -   4-6 is considered intermediate    -   7+ is considered indicative of BV.

In one group of embodiments, the present invention provides the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, (e.g. in either anoral or vaginal formulation), in combination with antifungal drugsactive against Candida albicans (including, but not limited tofluconazole, miconazole nitrate, clotrimazole, econazole, saperconazole,terconazole, fenticonazole, sertaconazole, posaconazole, itraconazole,ketoconazole, butaconazole, tioconazole, cyclopirox, caspofungin,micafungin, and anidulafungin) for the treatment of bacterial vaginitisor infections which are suspected to be due at least in part tobacterial vaginitis. The antifungal drug may be in the form of a vaginaltopical or systemic (e.g. oral) formulation. A single dose treatmentwith an oral sachet formulation of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole may be the only administration of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole for the entire treatment.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole do not effect thebeneficial lactobacilli species present in the vagina.

If present, the single dose treatment oral sachet formulation and thevaginal topical or systemic (e.g. oral) formulation of the antifungaldrug may be provided in the form of a kit.

This treatment is for strains of the causative bacterial pathogens thatare both sensitive and resistant to other antibacterial agents. In manycases the bacterial infection is either mixed with other protozoal orfungal infections or these infections induce each other by altering thenormal flora of the vagina. The present invention can allow moreconvenient empiric treatment as well as treatment when the presence ofboth fungal and bacterial or protozoal pathogens has been demonstrated.This can prevent secondary super-infections, reduce morbidity andmedical expense, and speed recovery. The fixed doses combination drugshave the necessary spectrum of activity to eradicate common causativebacterial, protozoal and fungal pathogens together for concurrenttreatment and also will have formulations appropriate to treatment ateither the vaginal site of infection, systemic infection, or both.

Treatment of Trichomoniasis

Trichomoniasis, sometimes referred to as “trich” is a sexuallytransmitted infection. The disease is caused by the single-celledprotozoan parasite Trichomonas vaginalis producing mechanical stress onhost cells and then ingesting cell fragments after cell death.Trichomoniasis is primarily an infection of the urogenital tract; themost common site of infection is the urethra and the vagina in women.Trichomoniasis is also associated with increased risk of transmission ofHIV.

In one group of embodiments, the present invention provides the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, (e.g. in either anoral or vaginal formulation), in combination with antifungal drugsactive against Candida albicans (including, but not limited tofluconazole, miconazole nitrate, clotrimazole, econazole, saperconazole,terconazole, fenticonazole, sertaconazole, posaconazole, itraconazole,ketoconazole, butaconazole, tioconazole, cyclopirox, caspofungin,micafungin, and anidulafungin) for the treatment of trichomoniasis orinfections which are suspected to be due at least in part totrichomoniasis. The antifungal drug may be in the form of a vaginaltopical or systemic (e.g. oral) formulation. A single dose treatmentwith an oral sachet formulation of (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole may be the only administration of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole for the entire treatment.

If present, the single dose treatment oral sachet formulation and thevaginal topical or systemic (e.g. oral) formulation of the antifungaldrug may be provided in the form of a kit.

This treatment is for strains of the causative bacterial pathogens thatare both sensitive and resistant to other antibacterial agents. In manycases the protozoal infection is either mixed with other bacterial orfungal infections or these infections induce each other by altering thenormal flora of the vagina. The present invention can allow moreconvenient empiric treatment as well as treatment when the presence ofboth fungal and protozoal pathogens has been demonstrated. This canprevent secondary super-infections, reduce morbidity and medicalexpense, and speed recovery. The fixed doses combinations will providethe drugs with necessary spectrum of activity to eradicate commoncausative bacterial, protozoal and fungal pathogens together forconcurrent treatment and also will have formulations appropriate totreatment at either the vaginal site of infection, systemic infection,or both.

Treatment of Bacterial Vaginosis Induced Yeast Infections

Yeast infections, also known as vaginal candidiasis, are fungalinfections of the vagina. They are most commonly due to the fungusCandida albicans. Candida albicans is a common type of fungus. It isoften present in small amounts in the vagina, mouth, digestive tract,and on the skin. Usually it does not cause disease or symptoms. Ingeneral, Candida and the many other germs or microorganisms thatnormally live in the vagina keep each other in balance. However, whenthe vagina has certain favorable conditions, the number of Candidaalbicans increases, leading to a yeast infection.

One these favorable conditions include a change the normal balancebetween organisms in the vagina by decreasing the number of protectivebacteria like Lactobacilli. This often occurs in a situation ofbacterial vaginosis. Hence, bacterial vaginosis, by reducing thepresence of lactic acid producing Lactobacilli and the breakdown of thevaginal mucosal barrier by other overgrowing bacterial species such asBacteroides species and Gardnerella species, predisposes these women togetting Vaginal candidiasis infections which often alternate withbacterial vaginosis infections and their treatment. If the underlyingcause of the fungal infection is a bacterial infection that creates asuitable environment for Candida overgrowth, then treatment of bacterialvaginosis with an effective antibacterial agent will also prevent theestablishment of yeast infections. Treatment with a combination of anantibiotic and an antifungal drug effective against Candida albicanswill both treat existing infections and will prevent new infections byallowing the re-establishment of the natural predominant Lactobacilliflora.

In one group of embodiments, the present invention provides the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole, (e.g. in either anoral or vaginal formulation), in combination with antifungal drugsactive against Candida albicans (including, but not limited tofluconazole, miconazole nitrate, clotrimazole, econazole, saperconazole,terconazole, fenticonazole, sertaconazole, posaconazole, itraconazole,ketoconazole, butaconazole, tioconazole, cyclopirox, caspofungin,micafungin, and anidulafungin) for the treatment of bacterial vaginosisrelated and induced vaginal yeast infections. The antifungal drug may bein the form of a vaginal topical or systemic (e.g. oral) formulation. Asingle dose treatment with an oral sachet formulation of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole may be the only administration of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole during the entiretreatment.

If present, the single dose treatment oral sachet formulation and thevaginal topical or systemic (e.g. oral) formulation of the antifungaldrug may be provided in the form of a kit.

This treatment is for strains of the causative bacterial pathogens thatare both sensitive and resistant to other antibacterial agents.

The present invention can allow more convenient empiric treatment aswell as treatment when the presence of both fungal and bacterialpathogens has been demonstrated. This can prevent secondarysuper-infections, reduce morbidity and medical expense, and speedrecovery. The combination drugs provide therapy with necessary spectrumof activity to eradicate common causative bacterial and fungal pathogenstogether for concurrent treatment and also will have formulationsappropriate to treatment at either the vaginal site of infection,systemic infection, or both.

Treatment of Odontogenic, Dental and Periodontal Infections

In one group of embodiments, the present invention provides therapeuticuses of (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in acombination product (e.g. a fixed dose combination product) with amacrolide (including, but not limited to erythromycin, clarithromycin, &azithromycin) antibiotic for the use of the treatment and/or prophylaxisof odontogenic, dental and periodontal infections, including, but notlimited to dental carries, peri-apical abscess, periodontal abscess, andacute peri-coronitis of impacted or partially erupted teeth.

In another group of embodiments, are provided formulations (e.g. oral orparenteral formulations) comprising (R)-ornidazole, (S)-ornidazole, and(rac)-ornidazole, alone or in combination with other antibiotics in thequinolone, beta lactam, and macrolide classes, for use in treatingodontogenic, dental and periodontal infections, including, but notlimited to dental carries, peri-apical abscess, periodontal abscess, andacute peri-coronitis of impacted or partially erupted teeth.

In yet another group of embodiments, is provided the use of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in a combinationproduct (e.g. a fixed dose combination product) with a beta lactamantibiotic for the prophylaxis and treatment of odontogenic, dental andperiodontal infections, including, but not limited to dental carries,peri-apical abscess, periodontal abscess, and acute peri-coronitis ofimpacted or partially erupted teeth.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst bacterial species including but not limited to Bacteroidesfragilis, Fusobacterium species, Peptostreptococcus species, Prevotellaspecies, Pophyromonas species, and Actinomyces species, the gramnegative bacteria which cause clinically relevant cases of dental andperiodontal infections and other antibiotic agents are active againstother causative species of bacteria in these infections.

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are highly activeagainst bacterial species including but not limited to biofilms ofBacteroides fragilis, Fusobacterium species, Peptostreptococcus species,Prevotella species, Pophyromonas species, and Actinomyces species, thegram negative bacteria which cause clinically relevant cases of dentaland periodontal infections and other antibiotic agents are activeagainst other causative species of bacteria in these infections.

In addition, the pharmacologic parameters of (R)-ornidazole,(S)-ornidazole, and (rac)-ornidazole make them appropriate to use in thesetting of the treatment the above enumerated dental and periodontalgram negative bacterial infections and their related indications.(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole are rapidlyabsorbed after oral administration and has a longer terminal eliminationhalf-life (approximately 14-18 hours) than commonly used drugs in theimidazole class. (R)-ornidazole, (S)-ornidazole, and (rac)-ornidazolehave an improved elimination half life that enables more convenientdosing of oral formulations for these above enumerated gram negativebacterial infections including sachet formulations of powder and orpelletized granules, capsules containing (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole, oral solid tablet formulations, and liquid oralsuspension formulations. These include sachet formulations with vehiclesfor varying absorbencies for delivery to different locations in thegastro-intestinal (GI) tract, capsules containing powders or pelletizedgranules with these properties, and oral solid tablet formulations withdifferent types of slow release properties. In many of the most severecases, parenteral formulations, such as (R)-ornidazole, (S)-ornidazole,and (rac)-ornidazole in hydrochloride form, are most appropriate forpatients in these certain clinical situations where oral formulationdelivery is not feasible or advisable. The disposition of(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole in the human bodyis similar for both oral and intravenous dosage forms and the presentinvention applies to the usage of both of these forms in these settings.

Summary of Organisms Against which (R)-Ornidazole, (S)-Ornidazole, and(Rac)-Ornidazole have Activity and Indications which they are Effectiveat Treating

(R)-ornidazole, (S)-ornidazole, and (rac)-ornidazole may be used in thetreatment of the following infections caused by both biofilms andplanktonic forms of susceptible isolates of anaerobic bacteria,Gram-negative bacteria and protozoa: genitourinary infections (includingbut not limited to vaginitis, trichomoniasis, urethritis, sexuallytransmitted urethritis, urinary tract infections, pyelonephritis,prostatitis, urosepsis, cystitis, Giardiasis), gastrointestinal and/orintra-abdominal infections (including but not limited to diverticulitis,psuedomembranous colitis, gastroenteritis, infectious/Clostridiumdifficile-associated diarrhea, cholangitis, cholecystitis, pancreatitis,peptic ulcer/bleeding, peritonitis, intra-abdominal/bowel/pelvicabscess), acute bacterial skin and skin structure infections (includingbut not limited to cellulitis, wound infections, rosacea, Lyme Disease,diabetic foot/leg ulcers, abscesses/boils/cysts, burns, gangrene),periodontal and dental infections, lower respiratory infections(including but not limited to nosocomial pneumonia, community-acquiredpneumonia, bronchitis), systemic and cardiovascular infections(including but not limited to septicemia, septic shock, bacteremia,endocarditis, indwelling catheter or device infections), bone and jointinfections (including but not limited to osteomyelitis, joint infection,septic arthritis), CNS infections (including but not limited tomeningitis, encephalitis, brain abscess), and upper respiratoryinfections (including but not limited to sinusitis, tonsillitis).

Table 1 gives a summary of various bacterial organisms and in whichclinical sites they are observed.

TABLE 1 Clinical sites of infection Soft Intra- Organism BV OralRespiratory tissue Pelvic abdominal Gram-negative organisms Bacteroidesfragilis + +++ ++ +++ Bacteroides thetaiotaomicron ++ +++Parabacteroides distasonis ++ +++ Fusobacterium gonidiaformans + ++Fusobacterium necrophorum + + +++ ++ + ++ Fusobacterium nucleatum + +++++ ++ + ++ Porphyromonas asaccharolytica ++ ++ ++ Porphyromonasgingivalis + +++ + + + Porphyromonas uenonis + ++ Prevotella amnii ++++++ Prevotella bivia +++ + +++ + Prevotella disiens +++ +++ Prevotellamelaninogenica +++ + ++ ++ +++ Prevotella timonensis +++ + +++Megasphaera 1&2 +++ Gram-positive organisms Gardnerella vaginalis +++Mobiluncus curtisii +++ Mobiluncus mulieris +++ Actinomycesisraelii + + + + Actinomyces neuii ssp neuii + + + + + Actinomycesodontolyticus + ++ + ++ + + Actinomyces radingae + ++ + + + +Actinomyces turicensis + ++ + ++ ++ ++ Peptostreptococcus anaerobius +++ ++ Peptoniphilus harei +++ + Peptoniphilus asaccharolyticus +++ +Peptoniphilus lacrimalis +++ + + + Anaerococcus tetradius +++ +Anaerococcus prevotii +++ + Finegoldia magna + +++ Atopobium vaginae ++++, infrequent; ++, sometimes; +++, frequently

(R)-Ornidazole and (S)-Ornidazole

The biological activity of the (R) and (S) enantiomer of Ornidazole maybe also enhanced against resistant strains of some of the organismswhich cause the infections described in this specification. The presentinvention of using this compound in these settings therefore provides ameaningful clinical benefit to patients through their eradication.

Additionally, the (R) and (S) enantiomers of Ornidazole in the presentinvention have a favorable hERG profile compared to the racemic mixtureas demonstrated in the hERG assay and thus may have a higher margin ofsafety.

Finally, the (R) and (S) enantiomers of Ornidazole in the presentinvention has a diminished effect on prothrombin time and thus may havea reduced bleeding risk relative to the Ornidazole racemic mixture whencombined with certain drugs effecting bleeding, like Warfarin.

The present invention of the (R) and (S) enantiomers of Ornidazole alsoprovides a process by which the (R) and (S) enantiomers of Ornidazolecan separately be synthesized specifically for therapeutic compositionsas well as a method by which the racemic mixture can be separated intoboth the (R) and (S) stereo-isomers by a process like synthesis from2-methyl-4-nitro-1H-imidazole by protection with chloromethyl acetate togive 1-acetoxymethyl-2-methyl-4-nitroimidazole(3), reacted with chiralcyclic sulfate followed by hydrolysis.

Features, integers, characteristics, compounds, chemical moieties orgroups described in conjunction with a particular aspect, embodiment orexample of the invention are to be understood to be applicable to anyother aspect, embodiment or example described herein unless incompatibletherewith. All of the features disclosed in this specification(including any accompanying claims, abstract and drawings), and/or allof the steps of any method or process so disclosed, may be combined inany combination, except combinations where at least some of suchfeatures and/or steps are mutually exclusive. The invention is notrestricted to the details of any foregoing embodiments. The inventionextends to any novel one, or any novel combination, of the featuresdisclosed in this specification (including any accompanying claims,abstract and drawings, such as attached FIG. 1 Syntheses), or to anynovel one, or any novel combination, of the steps of any method orprocess so disclosed.

The reader's attention is directed to all papers and documents which arefiled concurrently with or previous to this specification in connectionwith this application and which are open to public inspection with thisspecification, and the contents of all such papers and documents areincorporated herein by reference.

What is claimed is:
 1. (R)-ornidazole and (S)-ornidazole and the racemicmixture of (R)-ornidazole and (S)-ornidazole [rac-ornidazole], orpharmaceutically acceptable salts thereof, for use in the treatment orprophylaxis of disease associated with a dysbiosis of a microbialmicrobiome with bacteria, protozoa, and fungi in various morphologicalconformations, including biofilms, wherein the disease is selected fromthe group consisting of: Gastrointestinal tract disease, skin and softtissue diseases and infections, Lyme Disease, Glanders and Melioidosisinfections, Q-fever infections, systemic & cardiovascular infections,bone & joint infections, central nervous system (CNS) infections &conditions, upper and lower respiratory infections, skincontact/venereal sexually transmitted diseases (STDs), gynecological &genito-urinary/reproductive tract infections and conditions, anddental/periodontal infections.
 2. The compounds for use in claim 1,wherein the gastrointestinal tract disease is selected from the groupconsisting of psuedomembranous colitis, C. difficile infection caused bytoxigenic strains, C. difficile associated diarrhea caused by toxigenicstrains, gastroenteritis, chronic gastritis, cholangitis, cholecystitis,pancreatitis, peritonitis, intra-abdominal/bowel/pelvic/liver abscess,Crohn's disease, ulcerative colitis, colo-rectal cancer, gastric cancer,complicated and uncomplicated diverticulitis, and irritable bowelsyndrome.
 3. The compounds for use of claim 1, wherein thegastrointestinal tract disease is psuedomembranous colitis, C. difficileinfection caused by toxigenic strains, or C. difficile associateddiarrhea caused by biofilms and planktonic forms of toxigenic strains.4. The compounds for use of claim 1, wherein the disease is Crohn'sdisease, ulcerative colitis, chronic gastritis, gastroenteritis, orirritable bowel disease.
 5. The compounds for use of claim 1, whereinthe disease is colo-rectal cancer or gastric cancer.
 6. The compoundsfor use of claim 1, wherein the disease is complicated or uncomplicateddiverticulitis.
 7. The compounds for use of claim 1, wherein the diseaseis cholangitis, cholecystitis, pancreatitis, peritonitis, orabdominal/intra-abdominal/bowel/pelvic/liver abscess/infections, andirritable bowel syndrome.
 8. The compounds for use of any of claims 1 to7, wherein the infection is caused by biofilms of one or more organismsselected from the group consisting of Prevotella species, Bacteroidesspecies, toxigenic Clostridium species, Fusobacterium species,Peptococcus species, Peptostreptococcus species, and Helicobacterspecies.
 9. The compounds for use of claim 1, wherein the bacterialinfection is or gives rise to a dermatological condition.
 10. Thecompounds for use of claim 1, wherein the dermatological condition isselected from: rosacea, cellulitis, wound infections (e.g. gangrene),boils, cysts, abscesses, fungating tumors, burns, and decubitus ulcers(bed sores).
 11. The compounds for use of claim 1, wherein thedermatological condition is rosacea, for example rosacea associated withBacillus oleronius.
 12. The compounds for use of any one of claims 9 to11, wherein the Ornidazole compound is for topical administration. 13.The compounds for use of claim 1, wherein the use in the treatment ofLyme Disease.
 14. The compounds for use of claim 13, wherein the LymeDisease is caused by Borrelia spirochetes and at least some of theBorrelia spirochetes are present in a biofilm or in a cystic or roundhard body form.
 15. The compounds for use of claims 13-14, wherein theuse is for combination with one or more antibiotics, the antibioticsbeing selected from β-lactam antibiotics, tetracycline antibiotics andmacrolide antibiotics.
 16. The compounds for use of claim 1, wherein theuse is in the treatment of Glanders and Melioidosis infections.
 17. Thecompound for use of claim 16, wherein the Glanders and Melioidosisinfections are caused by biofilms of Burkholderia mallei or Burholderiapseudomallei and at least some of the bacteria are present in ananeroebic configuration.
 18. The compound for use of claims 16-17,wherein the Ornidazole compounds are for use in combination with one ormore antibiotics, the antibiotics being selected from β-lactamantibiotics, tetracycline antibiotics, penem antibiotics, quinoloneantibiotics and macrolide antibiotics.
 19. The compounds for use ofclaim 1, wherein the use is in the treatment of Q fever infections. 20.The compounds for use of claim 19, wherein the Q fever infection iscaused by Coxiella burnetii, a bacterium that affects humans and otheranimals, and at least some of the bacteria are a spore-like small cellvariant, and are obligate intracellular pathogens.
 21. The compounds foruse of claims 19-20, wherein the use is in combination with one or moreantibiotics, the antibiotics being selected from β-lactam antibiotics,tetracycline antibiotics, penem antibiotics, quinolone antibiotics andmacrolide antibiotics.
 22. The compounds for use of claim 1, wherein theuse in the treatment of a bacterial infection and related conditionsselected from the group consisting of systemic and cardiovascularinfections, bone and joint infections, CNS infections, upper and lowerrespiratory infections and lung infections.
 23. The compounds for use ofclaim 22, wherein the infection is selected from: septicemia, septicshock, bacteremia, endocarditis, indwelling catheter or deviceinfections, osteomyelitis, joint infection, septic arthritis,meningitis, encephalitis, autism, brain abscess, sinusitis, tonsillitis,lung abscess, emphysema, pneumonia (including noscomial, aspiration andcommunity acquired pneumonia), bronchitis, and Lemmiere's Syndrome. 24.The compounds for use of any of claims 22 to 23, wherein the infectionis caused by one or more organisms selected from the group consisting ofbiofilms of Prevotella species, Bacteroides species, Peptococcusspecies, Peptostreptococcus species, Clostridium, and Fusobacteriumspecies.
 25. The compounds for use of claim 1, wherein the use is fortreatment or prophylaxis/reduction in incidence of a skin contact orvenereal/sexually transmitted disease, wherein the disease is selectedfrom the group consisting of syphilis, yaws, and protozoal & bacterialurethritis.
 26. The compounds for use of claim 25, wherein the diseaseis syphilis.
 27. The compounds for use of claim 25, wherein the diseaseis yaws.
 28. The compounds for use of claim 25, wherein the disease isbacterial urethritis or trichomonal urethritis.
 29. The compounds foruse of claim 25, wherein one of the diseases specified cause venerialinfection resulting in premature rupture of membrane in pregnancy andpreterm labor (PRM/PTL).
 30. The compounds for use of any of claims 25to 29, wherein the infection is caused by one or more organisms selectedfrom the group consisting of biofilms of the spirochete bacteriumTreponema pallidum, subspecies pallidum and subspecies pertenue,Prevotella species, Bacteroides species, Peptococcus species,Peptostreptococcus species, Gardnerella vaginalis, Mobiluncus curtisii,Atopobium vaginae, and Clostridium species.
 31. The compounds for use ofclaim 1, wherein the use is for the treatment of a gynecological orgenitourinary bacterial infection selected from: prostatitis, urosepsis,urinary tract infections, pelvic inflammatory disease (PID),endometritis, endomyometritis, tubo-ovarian abscess, gynecologicalinfection resulting in premature rupture of membrane inpregnancy/preterm labor (PRM/PTL), and postsurgical vaginal cuffinfection.
 32. The compounds for use of claim 31, wherein thegynecological infection is selected from endometritis, endomyometritis,tubo-ovarian abscess, gynecological infection resulting in prematurerupture of membrane in pregnancy (PRM/PTL), and postsurgical vaginalcuff infection.
 33. The compounds for use of claim 31, wherein thegynecological or genitourinary infection is caused, at least in part, byan organism selected from biofilms of Gardnerella vaginalis, Mobiluncuscurtisii, Prevotella species, Bacteroides species, Atopobium vaginae,Peptococcus species, Peptostreptococcus species, and Clostridiumspecies.
 34. The compounds for use of any of claims 31 to 33, whereinthe genitourinary infection is bacterial urethritis and the use is inthe treatment of both women and men who are the sexual partners of womensuffering from multibacterial species infections like bacterialVaginosis and bacterial urethritis.
 35. The compounds for use of claim34, wherein the gynecological, genitourinary or vaginal infection isselected from bacterial vaginosis, vulvovaginitis, vaginal candidiasis(yeast infections), trichomoniasis, endometritis, endomyometritis,tubo-ovarian abscess and pelvic inflammatory disease (PID).
 36. Thecompounds for use of claims 31 or 35, wherein the gynecological orgenitourinary infection is caused, at least in part, by an organismselected from biofilms of Gardnerella vaginalis, Mobiluncus curtisii,Prevotella species, Bacteroides species, Atopobium vaginae, Peptococcusspecies, Peptostreptococcus species, and Clostridium species.
 37. Thecompounds for use of claim 1, wherein the use is for the treatment of anodontogenic, dental and periodontal bacterial infection.
 38. Thecompounds for use of claim 37, wherein the infection is selected from:dental carries, peri-apical abscess, periodontal abscess, and acuteperi-coronitis of impacted or partially erupted teeth.
 39. The compoundsfor use of claims 37 to 38, wherein the infection is caused by one ormore organisms selected from the group consisting of biofilms of:Bacteroides fragilis, Fusobacterium species, Peptostreptococcus species,Prevotella species, Porphyromonas species, and Actinomyces species. 40.The compounds for use of any of claims 37 to 39, wherein the compoundsare for systemic administration.
 41. (R)-ornidazole and (S)-ornidazoleand the racemic mixture of (R)-ornidazole and (S)-ornidazole[rac-ornidazole], or pharmaceutically acceptable salts thereof, for usein the treatment or prophylaxis of a disease, wherein the disease is oris caused by a protozoal infection.
 42. The compounds for use of claim41, wherein the protozoal infection is selected from trichmoniasis,giardiasis and amoebiasis.
 43. A method of stereoselectivelymanufacturing (R)-ornidazole and (S)-ornidazole; the method comprisingreacting 2-methyl-4(5)-nitroimidazole with (S)-propylene oxide.
 44. Themethod of claim 43, wherein the reaction is performed in the presence ofa Lewis acid.
 45. The method of claim 44, wherein the Lewis acid isZnCl₂.